Beta-cell Function In Subjects Research Articles

Co-segregation analysis and functional trial in vivo of candidate genes for monogenic diabetes

IntroductionThe aim of this study was to perform familial co-segregation analysis and functional trial in vivo during mixed meal tolerance test (MMTT) of novel variants in diabetes candidate genes.Research design...

Heterogeneity of beta-cell function in subjects with multiple islet autoantibodies in the TEDDY family prevention study - TEFA

BackgroundIndividuals with multiple islet autoantibodies are at increased risk for clinical type 1 diabetes and may proceed gradually from stage to stage complicating the recruitment to secondary prevention studies. We evaluated multiple islet autoantibody positive subjects before randomisation for a clinical trial 1 month apart for beta-cell function, glucose metabolism and continuous glucose monitoring (CGM). We hypothesized that the number and type of islet autoantibodies in combination with different measures of glucose metabolism including fasting glucose, HbA1c, oral glucose tolerance test (OGTT), intra venous glucose tolerance test (IvGTT) and CGM allows for more precise staging of autoimmune type 1 diabetes than the number of islet autoantibodies alone.MethodsSubjects (n = 57) at 2–50 years of age, positive for two or more islet autoantibodies were assessed by fasting plasma insulin, glucose, HbA1c as well as First Phase Insulin Response (FPIR) in IvGTT, followed 1 month later by OGTT, and 1 week of CGM (n = 24).ResultsAutoantibodies against GAD65 (GADA; n = 52), ZnT8 (ZnT8A; n = 40), IA-2 (IA-2A; n = 38) and insulin (IAA; n = 28) were present in 9 different combinations of 2–4 autoantibodies. Fasting glucose and HbA1c did not differ between the two visits. The estimate of the linear relationship between log2-transformed FPIR as the outcome and log2-transformed area under the OGTT glucose curve (AUC) as the predictor, adjusting for age and sex was − 1.88 (− 2.71, − 1.05) p = 3.49 × 10–5. The direction of the estimates for all glucose metabolism measures was positive except for FPIR, which was negative. FPIR was associated with higher blood glucose. Both the median and the spread of the CGM glucose data were significantly associated with higher glucose values based on OGTT, higher HbA1c, and lower FPIR. There was no association between glucose metabolism, autoantibody number and type except that there was an indication that the presence of at least one of ZnT8(Q/R/W) A was associated with a lower log2-transformed FPIR (− 0.80 (− 1.58, − 0.02), p = 0.046).ConclusionsThe sole use of two or more islet autoantibodies as inclusion criterion for Stage 1 diabetes in prevention trials is unsatisfactory. Staging type 1 diabetes needs to take the heterogeneity in beta-cell function and glucose metabolism into account.Trial registrationClinicalTrials.gov identifier: NCT02605148, November 16, 2015

Imatinib Therapy for Patients with Recent-Onset Type 1 Diabetes: A Randomised Blinded Phase 2 Trial

Background: Type 1 diabetes results from autoimmune-mediated destruction of beta cells. The tyrosine kinase inhibitor imatinib may impact relevant immunologic and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our goal was to evaluate the safety and efficacy of imatinib in preserving beta cell function in subjects with recent-onset type 1 diabetes. Methods: We conducted a phase 2, randomised, placebo-controlled, blinded clinical trial. Patients with recent-onset type 1 diabetes, aged 18-45 years, and with peak C-peptide ≥ 0.2 nmoles/L on mixed meal tolerance test (MMTT) were enrolled from 9 sites in the USA and Australia. Participants were randomly assigned 2:1 to receive either 400 mg imatinib or matching placebo for 26 weeks, respectively, using a computer-generated blocked randomisation scheme stratified by study site. The primary endpoint was the change in 2-hour area under the curve (AUC) C-peptide response to MMTT from baseline to 12 months, with further observation out to 24 months. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01781975. Findings: Patients were screened and enrolled into the trial between February 12, 2014 and May 19, 2016. 45 patients were assigned to imatinib, 22 to placebo. The study met its primary endpoint: the 12-mo C-peptide AUC mean was 0·583 (95% CI: 0·519, 0·650) nmoles/L in the imatinib group versus 0·489 (95% CI: 0·403, 0·579) nmoles/L for the placebo group, adjusted for baseline C-peptide, age, and gender (p = 0·048, 1-tail test). In secondary analyses, compared to the placebo group, imatinib-treated subjects required less exogenous insulin and trended towards lower HbA 1c , with higher beta cell glucose sensitivity, lower proinsulin/C-peptide ratios, improved insulin sensitivity, and higher serum adiponectin levels. No significant changes were noted in autoantibody titers and immune cell phenotyping. Interpretation: A 26-wk course of imatinib preserves beta cell function at 12 months in adults with recent onset type 1 diabetes. Although no overt effects on immune responses were detected, imatinib may have novel metabolic effects on both beta cell function and insulin sensitivity. Trial Registration: This study is registered with ClinicalTrials.gov, number NCT01781975. Funding: Juvenile Research Diabetes Foundation Declaration of Interests: SG has served on advisory boards for Avotres, Provention Bio, and Tolerion, and participated in clinical trials with Intrexon, Janssen, Provention Bio, and Tolerion. JB has consulted for Vertex Pharmaceuticals, Inc, and participated in clinical trials for Avotres, Caladrius, Janssen, and Tolerion. PG has served on advisory boards for Caladrius, Bristol Myers Squibb, and Lilly, received grant support from Caladrius, Novo Nordisk and Pfizer, and is co-founder and chief medica officer for ImmunoMolecular Therapeutics, Inc. RM has a patent application for DNA methylation in inflammatory disease. SW reports serving on advisory boards for Boehringer Ingelheim Pharmaceuticals, Inc. and Medtronic, and a DSMB for the National Institutes of Health. All other authors report no potential conflicts of interest. Ethics Approval Statement: This phase 2, randomised, placebo-controlled, double-blinded clinical trial was conducted according to the Declaration of Helsinki and in accordance with good clinical practice guidelines, performed under an investigational new drug application (IND 117644) and was approved by independent institutional review boards at each participating center.

Oral Glucose Tolerance Test with Insulin Assay and the evaluation of Insulin Resistance and Impaired Beta-cell function in primary prevention for Type 2 Diabetes

Background: Insulin resistance and impaired beta-cell function are associated with type 2 diabetes mellitus (T2DM). Many insulin resistance and beta-cell function indices have been developed using the data from an oral glucose tolerance test (OGTT) with insulin assay. However, insulin assays are not widely used along with the OGTT in primary prevention outpatient clinics. We aimed to evaluate the association of having impaired fasting glucose (IFG), impaired glucose tolerance (IGT), isolated or combined, with insulin resistance and impaired beta-cell function in subjects at risk for T2DM. Methods: This is a cross-sectional study that included 376 subjects who underwent an OGTT who had at least two risk factors for T2DM without any chronic disease. Results: Participants were 51.6±8.2 years old, 71.8% were women, had a mean body mass index (BMI) of 30.1±6.5 kg/m2, 42.4% had obesity and 26.7% hypertension. A HOMA-IR ≥2.5 was independently associated with male sex, BMI>25kg/m2, and with isolatedIFG, isolated-IGT, or combined (p<0.05 for all). On the other hand, only overweight, but not obesity, was independently associated with impaired beta-cell function (disposition index <1.24). Additionally, combined IFG and IGT had 29.7 higher odds to have impaired beta-cell function compared with those that had a normal OGTT. Conclusions: IFG alone, IGT alone, or the presence of both, are associated with higher odds to have insulin resistance and impaired beta-cell function in asymptomatic subjects at risk for T2DM without any chronic disease. Further studies are needed to evaluate this associations with the risk to develop T2DM, cardiovascular events and mortality.

Pancreatic Steatosis Associates With Impaired Insulin Secretion in Genetically Predisposed Individuals.

ContextPancreatic steatosis leading to beta-cell failure might be involved in type 2 diabetes (T2D) pathogenesis.ObjectiveWe hypothesized that the genetic background modulates the effect of pancreatic fat on beta-cell function and investigated genotype × pancreatic fat interactions on insulin secretion.DesignTwo observational studies.SettingUniversity hospital.Patients or participantsA total of 360 nondiabetic individuals with elevated risk for T2D (Tuebingen Family Study [TUEF]), and 64 patients undergoing pancreatectomy (Pancreas Biobank [PB], HbA1c <9%, no insulin therapy).Main Outcome MeasuresInsulin secretion calculated from 5-point oral glucose tolerance test (TUEF) and fasting blood collection before surgery (PB). A genome-wide polygenic score for T2D was computed from 484,788 genotyped variants. The interaction of magnetic resonance imaging-measured and histologically quantified pancreatic fat with the polygenic score was investigated. Partitioned risk scores using genome-wide significant variants were also computed to gain insight into potential mechanisms.ResultsPancreatic steatosis interacted with genome-wide polygenic score on insulin secretion (P = 0.003), which was similar in the replication cohort with histological measurements (P = 0.03). There was a negative association between pancreatic fat and insulin secretion in participants with high genetic risk, whereas individuals with low genetic risk showed a positive correlation between pancreatic fat and insulin secretion. Consistent interactions were found with insulin resistance-specific and a liver/lipid-specific polygenic scores.ConclusionsThe associations suggest that pancreatic steatosis only impairs beta-cell function in subjects at high genetic risk for diabetes. Genetically determined insulin resistance specifically renders pancreatic fat deleterious for insulin secretion.

Association of ghrelin dynamics with beta cell function in Japanese subjects with normal glucose tolerance.

Ghrelin is involved in feeding regulation and energy metabolism and is also known to inhibit insulin secretion (β). However, few clinical studies have demonstrated the relationship between β and ghrelin dynamics. This study tested the hypothesis that, in oral glucose tolerance tests (OGTT), ghrelin dynamics are associated with β. Subjects were 1145 healthy individuals <40years old who tested normal on the 75-g OGTT. The following indicators and the ghrelin suppression ratio (GSR) during OGTT were calculated: insulin sensitivity (SI) [1/homoeostasis model assessment of insulin resistance, insulin sensitivity index-Matsuda and 1/fasting insulin (1/FIRI)]; and β [Stumvoll first-phase index (Stumvoll-1), Stumvoll second-phase index and insulinogenic index]. From nine combinations of SI and β, combinations that produce hyperbolic relationships were identified. Stumvoll-1 and 1/FIRI showed a hyperbolic relationship in nonobese subjects, and the product of Stumvoll-1 and 1/FIRI was used as the disposition index (DI). When analyzed by BMI quartiles, post-loading glucose and insulin levels at each time point increased from Q1 (low BMI) through Q4 (high BMI), whereas the DI, ghrelin levels at each time point, and GSR decreased from Q1 to Q4. On multivariate and bivariate analysis, GSR and DI were positive and independent, and fasting ghrelin and FIRI were negatively and independently correlated. Ghrelin dynamics were associated with beta cell function in subjects with normal glucose tolerance. Glucose intolerance in obesity may be due not only to insulin resistance but also to impaired beta cell function associated with abnormalities of ghrelin dynamics.

Sodium-glucose co-transport 2 inhibitor decreases fasting plasma glucose level in impaired fasting glucose but not in normal glucose tolerance subjects

Renal sodium-glucose co-transport 2 inhibitor (SGLT2i) can reduce fasting plasma glucose (FPG) in patients with type 2 diabetes mellitus, but its effect on FPG and β-cell function in impaired fasting glucose (IFG) is unclear. The current article is the Chinses translation of an article entitled as Inhibition of Renal Sodium-Glucose Co-Transport with Empagliflozin Lowers Fasting Plasma and Improves Beta Cell Function in Subjects With Impaired Fasting Glucose , which was published in Diabetes in September [Diabetes, 2017, 66: 2495-2502], with the consent of Diabetes . Eight subjects with IFG and eight subjects with normal FPG (NFG) were included in the study. 9-stage high glucose clamp test was done before and 48 hours, 14 days after taking empagliflozin to quantitatively evaluate the effect of FPG reduction on islet β-cell function. The results showed that FPG concentration decreased only in IFG subjects from (110±2) to (103±3) mg/dl (P<0.01) after taking empagliflozin for 14 days, but the FPG remained unchanged [(95±2) to (94±2) mg/dl] in NFG subjects. The incremental area under the plasma C-peptide concentration curve during the hyperglycemic clamp increased by 22%±4% and 23%±4% in IFG subjects after 48 hours and 14 days, respectively (P<0.01); the plasma C-peptide response remained unchanged in NFG subjects. The insulin secretion/insulin sensitivity (disposition) index increased significantly in IFG, but not in NFG subjects. In conclusion, empagliflozin only reduces the FPG concentration and improves β-cell function in IFG. (Chin J Endocrinol Metab, 2017, 33: 874-879) Key words: Sodium-glucose co-transport 2 inhibitor; Empagliflozin; Fasting plasma glucose; β-cell function; Impaired fasting glucose.

The effects of once-weekly semaglutide on beta-cell function in subjects with type 2 diabetes

The effects of once-weekly semaglutide on beta-cell function in subjects with type 2 diabetes

Effects of potassium citrate or potassium chloride in patients with combined glucose intolerance: A placebo-controlled pilot study

BackgroundExperimental K+ depletion reversibly inhibits insulin secretion, while chronic metabolic acidosis decreases insulin sensitivity. We aimed to investigate the effects of potassium supplementation and alkali supplementation in non-acidotic, normokalemic humans with combined glucose intolerance. Study design and resultsIn this double-blind, placebo-controlled study in 11 subjects (7 male, 4 female, ages 47–63 years), 90meqs of oral KCl or Kcitrate per day for 2weeks each increased insulin production as measured by homeostasis model assessment Beta [KCl=86 (CI 81–91), Kcitrate=88 (82–94), placebo=78 (73–83)%, p<0.04], but only Kcitrate attenuated insulin resistance as assessed by HOMA-IR (insulin resistance, Kcitrate=2.8 (2.5–3.1), placebo=3.2 (2.9–3.5), p<0.03) and only Kcitrate increased quantitative insulin sensitivity check index (Quicki, Kcitrate=0.355 (0.305–0.405), placebo=0.320 (0.265–0.375) p<0.04). These results were confirmed by independent measurements, i.e. HOMA C-peptide and whole body insulin sensitivity index measured during oral glucose tolerance testing. Kcitrate significantly decreased systolic and diastolic 24-hour ambulatory blood pressures (−4.0 (−3 to −5) and −2.7 (−1.9 to −3.5), respectively as compared to placebo, p<0.02) while KCl was without a significant effect. ConclusionsK+ supplementation in the absence of overt K+ depletion improves beta-cell function in subjects with combined glucose intolerance. The insulin-sensitizing and hypotensive effect, however, depend on citrate as the accompanying anion.

Assessment of beta cell function in subjects with newly diagnosed type 2 diabetes

Assessment of beta cell function in subjects with newly diagnosed type 2 diabetes

Correlation between HDL cholesterol levels and beta-cell function in subjects with various degree of glucose tolerance

Some reports showed direct effects of high density lipoprotein cholesterol (HDL-C) on beta-cells survival and insulin secretion, suggesting an its role on glucose metabolism. We queried, whether subjects screened for type 2 diabetes (DM2) could display some impairment of beta-cell performance related to their HDL-C levels. A total of 1,087 clinical outpatients at risk of DM2 with no history of diabetes were studied. All participants were assessed for anthropometry, fasting lipid profile, and 2hOGTT with blood samples for plasma glucose and insulin determinations. Matsuda index of insulin sensitivity, early (insulinogenic index×Matsuda) and total (insulin secretion-sensitivity index-2 [ISSI-2]) indices of beta-cell function OGTT derived were applied. Linear regression analyzed the association between HDL-C levels and indices of beta-cell activity in subjects with normal glucose tolerance (NGT), impaired fasting glycemia (IFG), and impaired glucose tolerance (IGT). After adjustment for triglyceride levels, waist circumference, blood pressure and age, in total NGT subjects the HDL-C levels were not significantly associated with IGI×Matsuda (β=0.039, P=0.10) and ISSI-2 index (β=0.069, P=0.18), while in NGT with low HDL-C and IFG subjects the IGI×Matsuda (β=0.052, P=0.019) and ISSI-2 indices (β=0.061, P=0.023) were significantly associated with HDL-C levels. This significant linear correlation has been also observed in IGT patients for both indices (β=0.264, P=0.0001 and β=0.191, P=0.002, respectively). In conclusion, in subjects with impaired glucose regulation, HDL-C levels are associated with indices of beta-cell dysfunction; thus, more attention, it should be deserve to HDL-C concentrations in IFG/IGT patients due their potential conversion to DM2.

Glycated albumin to glycated hemoglobin ratio reflects postprandial glucose excursion and relates to beta cell function in both type 1 and type 2 diabetes

The glycated albumin (GA) to HbA1c ratio (GA/HbA1c ratio) has been proposed as a marker of postprandial glucose excursion. The aim of this study was to explore the correlation between the GA/HbA1c ratio and beta cell function. Three hundred sixteen subjects with type 2 diabetes who had been admitted to our hospital were examined. Blood samples were obtained after fasting and 2 h after breakfast. Beta cell function was assessed by the serum C-peptide immunoreactivity (CPR) to plasma glucose ratio. Similarly, the correlation between the GA/HbA1c ratio and beta cell function was also estimated in 61 subjects with type 1 diabetes. As a result, the GA/HbA1c ratio was significantly correlated with the postprandial plasma glucose (r = 0.274, p < 0.001) and postprandial increment of plasma glucose (r = 0.269, p < 0.001), but not fasting plasma glucose level (r = 0.081, p = 0.15). Among HbA1c, GA and GA/HbA1c ratio, the GA/HbA1c ratio showed the highest correlation with beta cell function in subjects with type 2 diabetes (r = −0.455, p < 0.001). A robust association between beta cell function and the GA/HbA1c ratio was shown by multiple regression analysis adjusting for confounders. Similar correlations were also observed in subjects with type 1 diabetes. In conclusion, we confirmed a negative association between beta cell function and the GA/HbA1c ratio, a marker of postprandial glucose excursion, in this study using a relatively large sample size. These results indicate that beta cell dysfunction is associated with larger glucose excursions in subjects with both type 1 and type 2 diabetes.

Failure of β-cell function for compensate variation in insulin sensitivity in hypomagnesemic subjects

To evaluate if decreased insulin sensitivity is appropriately compensated by beta-cell function in subjects with hypomagnesemia, 165 individuals, 20 to 65 years of age, were randomly enrolled in a cross-sectional study. Subjects were allocated into groups with and without hypomagnesemia, matched by age, gender, waist circumference, and body mass index. Pregnancy, smoking, alcohol consumption, high blood pressure, type 2 diabetes, chronic diarrhea, renal disease, malignancy, and heavy physical activity were exclusion criteria. Hypomagnesemia was defined by a serum magnesium concentration of < 1.8 mg/dL. As a surrogate of the hyperbolic model of beta-cell function, the relation between Belfiore's index {2/[1 + (Fasting insulin pmol/L x Fasting glucose mmol/L)]} and the HOMA-beta index {20 X Fasting insulin microU/mL /(Fasting glucose mmol/L - 3.5)} was used. The mean Area Under Curve (AUC) was calculated for each group. Although the Belfiore index was significantly lower (0.041 +/- 0.021 and 0.053 +/- 0.030, p = 0.005) and fasting plasma glucose higher (113.6 +/- 23.0 and 106.8 +/- 18.4 mg/dL, p = 0.04) in the subjects with hypomagnesemia, the HOMA-beta index (82.5 +/- 48.5 and 91.2 +/- 79.9, p = 0.32) and insulin levels (8.6 +/- 5.4 and 9.6 +/- 4.8 mciroU/mL, p = 0.17) were similar between the groups studied. The AUC which evaluates the adaptation of beta-cell function to variation in insulin sensitivity was significantly higher in the normo-magnesemic than the hypomagnesemic group (proportion 1:2.5). Results of this study show that the decrease in insulin sensitivity is not appropriately compensated by beta-cell function in individuals with hypomagnesemia; our finding suggests that hypomagnesemia could be linked to inadequate beta-cell compensation.

The anti‐interleukin‐1 in type 1 diabetes action trial—background and rationale

Type 1 diabetes (T1D) is caused by an inflammatory destruction of pancreatic beta-cells. Pro-inflammatory cytokines, in particular interleukin-1 (IL-1), have been suggested to be effector molecules based on the observations that pro-inflammatory cytokines cause beta-cell apoptosis in vitro and aggravate diabetes in vivo, and that inhibition of the action of these cytokines reduce diabetes incidence in animal models of type 1 diabetes and islet graft destruction. This review presents the rationale for and design of a recently launched double-blind, multicenter, randomized clinical trial that investigates the effect of interleukin-1 antagonism on beta-cell function in subjects with T1D of recent-onset.

Autoimmunity, Insulin Resistance and Beta Cell Function in Subjects with Low Body Weight Type 2 Diabetes Mellitus

In developing countries like India, the majority of Type 2 diabetics are non-obese, and many are "lean" with a body mass index (BMI) below 18.5. This type is referred to as "Low Body Weight Type 2 DM" (LB Type 2 DM). LB Type 2 DM are confused with Type 1 DM or late autoimmune diabetes in adults (LADA) due to their high blood glucose levels and early insulin-requiring state. We assessed pancreatic islet cell autoimmunity by using both glutamic acid decarboxylase 65 antibody (GADA) and anti-IA(2) antibody estimation in 23 patients with LB Type 2 DM and 10 age-matched normal weight (NW) Type 2 DM. Fasting blood glucose (FBG) and 2 hr postchallenge blood glucose (PGBG2) were significantly higher in LB (p < 0.05), while mean values of fasting insulin (24.47 +/- 73.15 muIU/mL vs. 13.4 +/- 16.54 muIU/mL, p > 0.7) and fasting C-peptide (180.81 +/- 357.08 pM/mL vs. 279.83 +/- 281.38 pM/mL, p > 0.5) in LB and NW respectively were not statistically different. All 23 LB and 10 NW subjects were GADA negative while IA(2) positivity was found in 1/23 and 1/10 cases, respectively. LB Type 2 DM revealed good beta cell function with homeostasis model assessment beta cells (HOMAB) values of 57.41 +/- 153.18 as compared to 44.74 +/- 56.24 (p > -0.2) in NW Type 2 DM. Insulin resistance as assessed by homeostasis model assessment insulin resistant (HOMA IR) was 13.50 +/- 42.83 and 5.68 +/- 6.90 (p > 0.6) in LB and NW Type 2 DM, respectively, suggesting that LB Type 2 DM are a phenotypic variant of Type 2 DM.

Six months of gluten-free diet do not influence autoantibody titers, but improve insulin secretion in subjects at high risk for type 1 diabetes.

Removal of gluten from the diet can attenuate the intensity of autoimmunity and reduces the incidence of diabetes in the nonobese diabetic mouse. In this study, we tested whether a gluten-free diet could reduce autoimmunity in human preclinical type 1 diabetes. A trial consisting of 6 months of a gluten-free diet followed by another 6 months of normal gluten-containing diet was performed in 17 first-degree relatives with at least 2 antibodies among islet cell antibodies, glutamic acid decarboxylase autoantibodies, protein tyrosine islet antigen-2 autoantibodies, and insulin autoantibodies. Treatment effect was measured as autoantibody titers and acute insulin response to iv glucose tolerance test. Two subjects dropped out for lack of compliance to diet restrictions. Of the remaining 15 subjects, 3 developed diabetes. Autoantibody titers did not show significant changes after 6 months of gluten-free diet and again after return to normal diet. Acute insulin response to iv glucose tolerance test significantly increased in 12 of 14 subjects after the first 6 months of gluten deprivation (P = 0.04) and decreased in 10 of 13 subjects during the following 6-month period of normal diet (P = 0.07). Insulin sensitivity (homeostasis model assessment-insulin resistance) nonsignificantly improved after the gluten-free diet and subsequently decreased (P < 0.005) after 6 months of normal diet. These findings indicate that 6 months of gluten deprivation do not influence humoral autoimmunity, but may have a beneficial effect on preservation of beta-cell function in subjects at risk for type 1 diabetes.

Compensation in pancreatic beta-cell function in subjects with glucokinase mutations

Compensation in pancreatic beta-cell function in subjects with glucokinase mutations