The pathophysiology of glucose intolerance in newly diagnosed, untreated T2DM.

AIMS: The two predominant pathophysiological defects resulting in glucose intolerance are beta-cell dysfunction and insulin insensitivity. This study aimed to re-examine beta-cell function and insulin sensitivity across a continuum from normal glucose tolerance (NGT) to early type 2 diabetes (T2DM) employing highly specific insulin, C-peptide and intact proinsulin assays. MATERIALS AND METHODS: A total of 104 persons with NGT, 85 with impaired glucose tolerance (IGT) and 554 with newly diagnosed T2DM were investigated. Following an overnight fast, all underwent a 4-h standardised mixed meal tolerance test (MTT), and on a second day, a sub-group underwent a frequently sampled insulin-modified intravenous glucose tolerance test (FSIVGTT) over a 3-h period. The participants were stratified according to fasting glucose and BMI for analysis. RESULTS: The MTT revealed that increasing FPG was accompanied by progressively elevated and delayed postprandial glucose peaks. In parallel, following an initial compensatory increase in fasting and postprandial insulin responses there followed a progressive demise in overall beta-cell secretory capacity. FSIVGTT demonstrated a major reduction in the early insulin response to IV glucose in persons with IGT accompanied by a dramatic fall in insulin sensitivity. Beyond pre-diabetes, ever-increasing fasting and postprandial hyperglycaemia resulted predominantly from a progressively decreasing beta-cell secretory function. CONCLUSION: This study utilising improved assay technology re-affirms that beta-cell dysfunction is evident throughout the spectrum of glucose intolerance, whereas the predominant fall in insulin sensitivity occurs early in its evolution.

Real-World Clinical Experience of Semaglutide in Secondary Care Diabetes: A Retrospective Observational Study.

INTRODUCTION: The glucagon-like peptide-1 receptor analogue (GLP-1RA) semaglutide is associated with improvements in glycaemia and cardiovascular risk factors in clinical trials. The aim of this study was to examine the real-world impact of semaglutide administered by injection in people with type 2 diabetes (T2D) across three secondary care sites in Wales. METHODS: A retrospective evaluation of 189 patients with T2D initiated on semaglutide between January 2019 and June 2020 with at least one follow-up visit was undertaken. RESULTS: At baseline, participants had a mean age of 61.1 years, mean glycated haemoglobin (HbA1c) of 77.8 mmol/mol (9.3%) and mean body weight of 101.8 kg. At 6 and 12 months of follow-up, mean HbA1c reductions of 13.3 mmol/mol (1.2%) and 16.4 mmol/mol (1.5%), respectively, were observed, and mean weight loss at 6 months was 3.0 kg (all p < 0.001). At 12 months, there were significant reductions in total cholesterol (0.5 mmol/L) and alanine transaminase (4.8 IU/L). Patients naïve to GLP-1RAs or with higher baseline HbA1c at baseline had greater glycaemic reductions, although clinically significant HbA1c reductions were also observed in those who switched from other GLP-1RAs, whose body mass index was < 35.0 and > 35.0 kg/m2 or who had lower baseline HbA1c. Semaglutide was generally well tolerated, although adverse-effects limited use in 18 patients (9.5%). CONCLUSION: Semaglutide provided clinically and statistically significant reductions in HbA1c, body weight, lipids and liver enzymes.

Safety of injectable semaglutide for type 2 diabetes.

INTRODUCTION: Semaglutide is the most recently approved injectable glucagon-like peptide-1 receptor agonist (GLP-1RA) for people with type 2 diabetes (T2DM). It is one of the three currently marketed GLP-1RAs that can be administered once weekly. AREAS COVERED: This review focusses on the safety of injectable semaglutide. Semaglutide has been assessed in the SUSTAIN phase 3 clinical trial programme, which included patients across the disease spectrum, i.e. treatment-naïve to those receiving insulin. The authors have looked at all published literature on safety considerations of once weekly GLP-1RA with particular reference to semaglutide. EXPERT OPINION: Semaglutide is the most powerful injectable GLP-1RA. The cardiovascular (CV) outcome trial (SUSTAIN 6) showed CV superiority and its adverse event profile is as expected for the GLP-1RA class with predominantly gastrointestinal side-effects. Concerns about the thyroid and pancreatic safety have not been substantiated. There is no indication of renal or liver harm for semaglutide. Data consistent with reno-protection and benefit in liver disease is presented. There is a modest signal for increased gall bladder adverse events. An increase in diabetic retinopathy (DR) events in the SUSTAIN 6 trial is the most concerning safety signal. Caution regarding DR is needed when initiating semaglutide and recommendations are suggested.

Cost-effectiveness of biennial screening for diabetes related retinopathy in people with type 1 and type 2 diabetes compared to annual screening.

OBJECTIVE: Examine the health and economic impact of extending screening intervals in people with Type 2 diabetes (T2DM) and Type 1 diabetes (T1DM) without diabetes-related retinopathy (DR). SETTING: Diabetic Eye Screening Wales (DESW). STUDY DESIGN: Retrospective observational study with cost-utility analysis (CUA) and Decremental Cost-Effectiveness Ratios (DCER) study. INTERVENTION: Biennial screening versus usual care (annual screening). INPUTS: Anonymised data from DESW were linked to primary care data for people with two prior screening events with no DR. Transition probabilities for progression to DR were estimated based on a subset of 26,812 and 1232 people with T2DM and T1DM, respectively. DCER above £20,000 per QALY was considered cost-effective. RESULTS: The base case analysis DCER results of £71,243 and £23,446 per QALY for T2DM and T1DM respectively at a 3.5% discount rate and £56,822 and £14,221 respectively when discounted at 1.5%. Diabetes management represented by the mean HbA1c was 7.5% for those with T2DM and 8.7% for T1DM. SENSITIVITY ANALYSIS: Extending screening to biennial based on HbA1c, being the strongest predictor of progression of DR, at three levels of HbA1c 6.5%, 8.0% and 9.5% lost one QALY saving the NHS £106,075; £58,653 and £31,626 respectively for T2DM and £94,696, £37,646 and £11,089 respectively for T1DM. In addition, extending screening to biennial based on the duration of diabetes > 6 years for T2DM per QALY lost, saving the NHS £54,106 and for 6-12 and > 12 years for T1DM saving £83,856, £23,446 and £13,340 respectively. CONCLUSIONS: Base case and sensitivity analyses indicate biennial screening to be cost-effective for T2DM irrespective of HbA1c and duration of diabetes. However, the uncertainty around the DCER indicates that annual screening should be maintained for those with T1DM especially when the HbA1c exceeds 80 mmol/mol (9.5%) and duration of diabetes is greater than 12 years.

Proinsulin in the identification and risk stratification of gestational diabetes mellitus: study protocol for a prospective, longitudinal cohort study.

INTRODUCTION: Gestational diabetes mellitus (GDM) is a common metabolic disorder occurring in up to 10% of pregnancies in the western world. Most women with GDM are asymptomatic; therefore, it is important to screen, diagnose and manage the condition as it is associated with an increased risk of maternal and perinatal complications. Diagnosis of GDM is made in the late second trimester or early third trimester because accurate diagnosis or risk stratification in the first trimester is still lacking. An increase in serum proinsulin may be seen earlier in pregnancy and before a change in glycaemic control can be identified. This study will aim to establish if fasting proinsulin concentrations at 16-18 weeks gestation will help to identify or risk stratify high-risk pregnant women with GDM. METHODS AND ANALYSIS: This is a prospective, longitudinal cohort study. Two oral glucose tolerance tests will be carried out at 16-18 and 24-28 weeks gestation in 200 pregnant women with at least one risk factor for GDM (body mass index>30 kg/m2, previous macrosomic baby (>4.5 kg), previous gestational diabetes, first degree relative with type 2 diabetes mellitus) recruited from antenatal clinics. Blood samples will be taken fasting and at 30 min, 1 and 2 hours following the 75 g glucose load. In addition, a fasting blood sample will be taken 6-weeks post delivery. All samples will be analysed for glucose, insulin, C peptide and proinsulin. Recruitment began in November 2017. Optimal cut-off points for proinsulin to diagnose gestational diabetes according to National Institute for Health and Care Excellence (2015) criteria will be established by the receiver operating characteristic plot and sensitivity and specificity will be calculated to assess the diagnostic accuracy of proinsulin at 16-18 weeks gestation. ETHICS AND DISSEMINATION: This study received ethical approval from the Wales Research Ethics Committee (Panel 6) (Ref. 17/WA/0194). Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN16416602; Pre-results.

Stability of proinsulin in whole blood.

Proinsulin, the precursor for insulin, is secreted in higher concentrations when ß-cells are under stress and previous studies have shown that elevated proinsulin could be used as a marker for individuals in a pre-diabetic state. The aim of this study was to assess the stability of proinsulin across a wide concentration range (3-882 and 2-187pmol/L; total and intact proinsulin respectively) in whole blood to determine whether it could be used in routine clinical care. 51 subjects (26 normal glucose tolerance, 17 impaired glucose tolerance and 8 type 2 diabetes) had blood taken into EDTA tubes at 0, 60 & 120min following a glucose load. The samples were kept at room temperature (~20°C) with aliquots taken, centrifuged and frozen at 0, 24, 48 and 72h. Comparison of the combined data (pre and post-glucose load) of baseline with 72h as a percentage of baseline gave an average of 123% (95% CI: 119-127) and 107% (95% CI: 105-109) for total and intact proinsulin respectively. A small change in the stability of total proinsulin was observed whilst there was no clinical difference over the 72h period for intact proinsulin.

Diabetic Retinopathy in Newly Diagnosed Subjects With Type 2 Diabetes Mellitus: Contribution of ß-Cell Function.

PURPOSE: The association of hyperglycemia and diabetic retinopathy (DR) in established type 2 diabetes mellitus (T2DM) subjects is well accepted. However, the association between ß-cell responsiveness and insulin sensitivity leading to fasting and postprandial hyperglycemia with DR in newly diagnosed treatment-naïve T2DM subjects remain unreported. METHODS: A total of 544 newly diagnosed treatment-naïve T2DM subjects were screened for DR (digital photography) and underwent a standardized meal tolerance test. Serial plasma glucose and insulin levels were measured, and fasting (M0) and postprandial ß-cell responsiveness calculated Calculating Pancreatic Response Program along with homeostasis model assessment-ß cell function (HOMA-B) and HOMA-Insulin Sensitivity. A subgroup of 201 subjects also underwent a frequently sampled IV glucose tolerance test and the acute insulin response to glucose, insulin sensitivity, and glucose effectiveness (SG) estimated (MINMOD model). RESULTS: A total of 16.5% (90) subjects had DR at diagnosis. Subjects with DR had significantly reduced M0, HOMA-B and SG leading to higher fasting and postprandial (2 hour) glucose and significantly lower fasting and postprandial (2 hour) insulin. Factors independently associated with DR in multivariate logistic regression analysis were M0, HOMA-B, and SG with fasting and postprandial (2 hour) glucose and insulin. There was no statistical difference in glycated hemoglobin, systolic blood pressure, acute insulin response to glucose, and insulin sensitivity between those with or without DR. PRINCIPAL CONCLUSIONS: In this cohort of newly diagnosed T2DM subjects, DR is associated with reduced ß-cell responsiveness, resulting from ß-cell failure rather than insulin resistance, leading to fasting and postprandial hyperglycemia and hypoinsulinemia.

Can admission and fasting glucose reliably identify undiagnosed diabetes in patients with acute coronary syndrome?

OBJECTIVE: Our objectives were to determine the prevalence of previously undiagnosed abnormal glucose tolerance, i.e., diabetes and impaired glucose tolerance (IGT) in patients with acute coronary syndrome and to assess the utility of admission and fasting glucose in identifying diabetes in these patients. RESEARCH DESIGN AND METHODS: Glycemic status was characterized on the basis of admission plasma glucose (APG), fasting plasma glucose (FPG), and an oral glucose tolerance test (OGTT) in 140 patients admitted to the hospital with acute coronary syndrome, who were not known to have diabetes (mean +/- SD age 67.3 +/- 13.4 years; 79% men). OGTTs were performed on days 5-7 after admission. RESULTS: The prevalences of diabetes and IGT were 27 and 39%, respectively, according to OGTT criteria. Receiver operating characteristic curves showed that the area under the curve for diagnosing diabetes was 0.83 (P < 0.001) for FPG, 0.79 (P < 0.001) for APG, and 0.84 (P < 0.001) for FPG and APG applied in combination. A FPG cutoff >or=5.6 mmol/l (100 mg/dl) and/or APG >or=7.8 mmol/l (140 mg/dl) yielded a sensitivity of 89.5% and a positive predictive value of 43.6% for detecting diabetes. CONCLUSIONS: A high prevalence of abnormal glucose tolerance was seen in patients with acute coronary syndrome. The combination of FPG >or=5.6 mmol/l (100 mg/dl) and/or APG >or=7.8 mmol/l (140 mg/dl) was highly sensitive for identifying diabetes. Although weakly specific, this simple algorithm could offer a practical initial screening tool at the acute setting in the high-risk population with acute coronary syndrome.

A comparison of preprandial insulin glulisine versus insulin lispro in people with Type 2 diabetes over a 12-h period.

A comparison of the plasma glucose and insulin day profiles between two prandial rapid-acting insulin analogues, insulin glulisine (glulisine) and insulin lispro (lispro), in 18 obese subjects with Type 2 diabetes. Subjects (body mass index: males, 36.7 [33.2-43.8] kg/m(2); females, 40.0 [35.7-46.5] kg/m(2)) received subcutaneous glulisine or lispro (0.15 U/kg) at 4-h intervals immediately (within 2 min) before three standard test meals during each of two 12-h, randomised, open-label, crossover studies (7+/-2-day interval between each). Overall, preprandial-subtracted glucose concentrations (area under the curve) were similar on the glulisine and lispro study days. However, the mean of the three maximal preprandial subtracted plasma glucose concentrations (DeltaGLU(max)) were lower with glulisine versus lispro (12%; p<0.01). Mean concentrations of insulin analogue were significantly higher post-meal with glulisine (p<0.01 for all). Post hoc analysis showed a significantly faster absorption rate for glulisine versus lispro in the first 30 min post-meal (estimated difference 0.48 microU/min; p<0.0001). Only two cases of hypoglycaemia were reported; both from one subject during the lispro day. When glulisine is injected immediately before a meal in obese patients with Type 2 diabetes, glulisine achieves significantly lower glucose excursions over lispro. Significantly faster absorption with higher and sustained post-meal levels of insulin analogue was achieved at every meal with glulisine versus lispro.

PTH circadian rhythm and PTH target-organ sensitivity is altered in patients with adult growth hormone deficiency with low BMD.

UNLABELLED: AGHD is associated with osteoporosis. We examined PTH circadian rhythmicity and PTH target-organ sensitivity in 23 patients with AGHD with low BMD and 20 patients with AGHD with normal BMD. Patients with low BMD had a blunted nocturnal rise in PTH concentration and reduced PTH target-organ sensitivity compared with patients with normal BMD; these factors may be important in the pathogenesis of AGHD-related osteoporosis. INTRODUCTION: Adult growth hormone deficiency (AGHD) is associated with decreased BMD. Reduced parathyroid gland sensitivity to changes in calcium and reduced PTH target-organ sensitivity may underlie the pathogenesis of AGHD-related osteoporosis. A blunted nocturnal PTH rise has been reported in AGHD and may contribute to the reduction in BMD. We examined the difference in PTH concentration and markers of bone metabolism in patients with AGHD with normal and low BMD. MATERIALS AND METHODS: Forty-three patients with AGHD consented to the study. Twenty-five patients were growth hormone (GH) naïve (GH-N, 13 had BMD femoral neck or lumbar spine T-score < -1.0), and 18 patients had received GH for >2 yr (GH-R, 10 had BMD T-score < -1.0). Patients were hospitalized for 24 h, where blood samples were collected every 0.5 h and urine samples were collected every 3 h for PTH, calcium, phosphate, NcAMP, 1,25-dihydroxyvitamin D [1,25(OH)(2)D], type-I collagen beta C-telopeptide (betaCTX), and procollagen type-I amino-terminal propeptide (PINP). Serum calcium was adjusted for albumin (ACa). RESULTS: Low BMD GH-N and GH-R patients exhibited a reduced nocturnal rise in PTH concentration compared with patients with normal BMD (p < 0.001). GH-N low BMD patients had significantly higher 24-h mean PTH (p < 0.001) than GH-N normal BMD patients, with significantly lower 24-h mean NcAMP, ACa, and 1,25(OH)(2)D (p < 0.01), suggesting a reduction in renal PTH sensitivity. GH-R low BMD patients had significantly lower 24-h mean PTH, NcAMP, ACa, and 1,25(OH)(2)D (p < 0.01) than GH-R normal BMD patients, suggesting reduced renal PTH action. Lower PTH concentration in the presence of lower ACa may reflect reduced sensitivity of the parathyroid calcium-sensing receptor to changes in ACa concentration in the GH-R low BMD patients. CONCLUSIONS: Low BMD in GH-N and GH-R AGHD patients may be a consequence of abnormalities in PTH circadian rhythmicity together with reduced parathyroid gland and target-organ sensitivity. Further studies are needed to determine the potential benefit of therapeutic manipulation of PTH rhythmicity and sensitivity on BMD.

Effects of exercise on the absorption of insulin glargine in patients with type 1 diabetes.

OBJECTIVE: To study the effects of exercise on the absorption of the basal long-acting insulin analog insulin glargine (Lantus), administered subcutaneously in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 13 patients (12 men, 1 woman) with type 1 diabetes on a basal-bolus insulin regimen were studied. (125)I-labeled insulin glargine at the usual basal insulin dose was injected subcutaneously into the thigh on the evening (2100) before the study day on two occasions 1 week apart. Patients were randomly assigned to 30 min intense exercise (65% peak oxygen uptake [Vo(2peak)]) on one of these visits. The decay of radioactive insulin glargine was compared on the two occasions using a thallium-activated Nal gamma counter. Blood samples were collected at regular intervals on the study days to assess plasma glucose and insulin profiles. RESULTS: No significant difference was found in the (125)I-labeled insulin glargine decay rate on the two occasions (exercise vs. no exercise; repeated-measures ANOVA, P = 0.548). As expected, a significant fall in plasma glucose was observed over the exercise period (area under curve above fasting [DeltaAUC] glucose: -0.39 +/- 0.11 vs. -1.30 +/- 0.16 mmol . l(-1) . h(-1); nonexercise vs. exercise; P = 0.001), but insulin levels did not differ significantly on the two occasions (DeltaAUC insulin: -2.1 +/- 3.9 vs. 1.5 +/- 6.2 pmol . l(-1) . h(-1); nonexercise versus exercise; P = 0.507). CONCLUSIONS: An intense 30-min period of exercise does not increase the absorption rate of the subcutaneously injected basal long-acting insulin analog insulin glargine in patients with type 1 diabetes.