Intermittently scanned continuous glucose monitoring provides no benefit over structured self-monitoring of blood glucose in type 2 diabetes not on prandial insulin, in the context of diabetes self-management education: GLucose monitoring programme SingaporE (GLiMPSE).

OBJECTIVE: We evaluated the impact of intermittently scanned continuous glucose monitoring(is-CGM)over self-monitoring of blood glucose(SMBG) in the context of diabetes self-management education (DSME) in sub-optimally controlled type 2 diabetes(T2D) in a multi-ethnicsetting. RESEARCH DESIGN AND METHOD: Randomized-controlled, open-label trial (NCT04564911), of T2D with HbA1c ≥ 7.5-≤10 %, on oral agents with/without basal insulin was carried out. Intervention arm received 6 weeks(w) continuous is-CGM, followed by one is-CGM/month till 24w. Control arm was advised to perform 4 SMBG/day. Educationwas delivered at weeks 0, 2, 8, 16. PRIMARY OUTCOME: Change in HbA1c from baseline at 24w. Modified intention-to-treat (mITT) analysis with linear mixed-effect model for repeated measurementswas performed. RESULTS: 176 subjects, age 55 ± 10.7 years(y), DM duration 11 ± 7.3y, BMI 27.8 ± 5.9 kg/m2, 58 % Male, 29.5 % basal insulin users were analysed. Within each arm,from baseline to 24w, mean HbA1c decreasedby -0.6 % (-6.6.mmol/mol, p-value < 0.01)and weight decreased(isCGM: -1.44 kg; SMBG: -1.25 kg, both p < 0.01). These changes were sustained to one year. However, there wasno significant difference in these parameters between arms (p-value > 0.05). CONCLUSION: In the context of DSME, use of either SMBG or is-CGM led to improved glycaemia and reduced weight over a period of 24 weeks, sustained to one year.

Fulminant type 1 diabetes, an underrecognized and unique subtype of type 1 diabetes: A case series from Singapore.

Fulminant type 1 diabetes (FT1D) is a unique subtype of type 1 diabetes, characterized by acute absolute insulin deficiency, severe ketosis, and increased risk of hypoglycemia, glycemic variability and microvascular complications. Seven people with FT1D were identified from two tertiary centers in Singapore. Six were Chinese, the mean age was 35 years and all were lean (mean body mass index 20.3 kg/m2 ). All presented with diabetes ketosis or ketoacidosis and low C-peptide. All but one had low glutamic acid decarboxylase antibodies. Nearly half had a missed/delayed diagnosis of FT1D. Three had frequent hypoglycemia, which improved after transition to continuous subcutaneous insulin infusion therapy. Individuals with FT1D experience unique diagnostic and management challenges associated with rapid absolute insulin deficiency. Greater awareness about this clinical entity is required.

Protocol update and baseline characteristics for the TRIal to slow the Progression of Diabetes (TRIPOD) randomized controlled trial.

BACKGROUND: Type 2 diabetes (T2D), a major risk factor for cardiovascular disease and other adverse health conditions, is on the rise in Singapore. TRIPOD is a randomized controlled trial aimed to determine whether complementing usual care with an evidence-based diabetes management package (DMP) -comprising access to an evidence-based app, health coaching, pedometer, glucometer and weighing scale, with or without a financial rewards scheme (M-POWER rewards), can improve mean HbA1c levels at months 6 and 12. METHODS: The protocol was published in Trials, accessible via https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3749-x 1. This manuscript updates the protocol with changes to the study design due to challenges with recruitment and presents baseline characteristics. Key updates include changing the arm allocation ratio from 1:1:1 (Arm 1-Usual Care: Arm 2-DMP: Arm 3-DMP+M-POWER rewards) to 10:1:10, the sample size from 339 to 269, the intervention period from two to one year, and the primary hypothesis to focus solely on differences between Usual Care and DMP+M-POWER rewards. Recruitment for the study began on 19 October 2019 and ended on 4 June 2022. RESULTS: The average age of participants was 55.0 (SD9.7) years old and 64.2% were male. The majority of participants (76.8%) were Chinese, 4.9% Malay and 18.3% Indian and of other ethnicities. 67.0% had a monthly household income of SGD$4000 or more. The mean baseline HbA1c was 8.10% (SD 0.95) and the mean body mass index was 26.8 kg/m2 (SD 5.3). DISCUSSION: The final participant completed month 12 follow-up data collection on 8 June 2023. All pre-planned analyses will be conducted and final results reported. TRIAL REGISTRATION: ClinicalTrials.gov NCT03800680 . Registered on 11 January 2019.

PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development.

The coding variant (p.Arg192His) in the transcription factor PAX4 is associated with an altered risk for type 2 diabetes (T2D) in East Asian populations. In mice, Pax4 is essential for beta cell formation but its role on human beta cell development and/or function is unknown. Participants carrying the PAX4 p.His192 allele exhibited decreased pancreatic beta cell function compared to homozygotes for the p.192Arg allele in a cross-sectional study in which we carried out an intravenous glucose tolerance test and an oral glucose tolerance test. In a pedigree of a patient with young onset diabetes, several members carry a newly identified p.Tyr186X allele. In the human beta cell model, EndoC-ßH1, PAX4 knockdown led to impaired insulin secretion, reduced total insulin content, and altered hormone gene expression. Deletion of PAX4 in human induced pluripotent stem cell (hiPSC)-derived islet-like cells resulted in derepression of alpha cell gene expression. In vitro differentiation of hiPSCs carrying PAX4 p.His192 and p.X186 risk alleles exhibited increased polyhormonal endocrine cell formation and reduced insulin content that can be reversed with gene correction. Together, we demonstrate the role of PAX4 in human endocrine cell development, beta cell function, and its contribution to T2D-risk.

Risk prediction models for type 2 diabetes using either fasting plasma glucose or HbA1c in Chinese, Malay, and Indians: Results from three multi-ethnic Singapore cohorts.

AIMS: To assess three well-established type 2 diabetes (T2D) risk prediction models based on fasting plasma glucose (FPG) in Chinese, Malays, and Indians, and to develop simplified risk models based on either FPG or HbA1c. METHODS: We used a prospective multiethnic Singapore cohort to evaluate the established models and develop simplified models. 6,217 participants without T2D at baseline were included, with an average follow-up duration of 8.3 years. The simplified risk models were validated in two independent multiethnic Singapore cohorts (N = 12,720). RESULTS: The established risk models had moderate-to-good discrimination (area under the receiver operating characteristic curves, AUCs 0.762 - 0.828) but a lack of fit (P-values < 0.05). Simplified risk models that included fewer predictors (age, BMI, systolic blood pressure, triglycerides, and HbA1c or FPG) showed good discrimination in all cohorts (AUCs ≥ 0.810), and sufficiently captured differences between the ethnic groups. While recalibration improved fit the simplified models in validation cohorts, there remained evidence of miscalibration in Chinese (p ≤ 0.012). CONCLUSIONS: Simplified risk models including HbA1c or FPG had good discrimination in predicting incidence of T2D in three major Asian ethnic groups. Risk functions with HbA1c performed as well as those with FPG.

Telemonitoring With a Connected Glucose Meter Improves Glycemia Among People With Insulin-Treated Type 2 Diabetes.

BACKGROUND: Delayed initiation and inadequate titration remain critical challenges to optimizing insulin therapy in type 2 diabetes (T2D). We aimed to study whether hemoglobin A1c (HbA1c) can be lowered in people with insulin-treated T2D using telemonitoring. METHODS: This single-center study recruited adults with greater than or equal to six months of diabetes, greater than or equal to three months of insulin therapy, HbA1c ≥8.5% and ≤12.5%, and body mass index (BMI) ≤40 kg/m2. All participants received a connected glucose meter and the accompanying smartphone application. Participants sent weekly blood glucose (BG) diary to their primary endocrinologist via email. Adjustments in insulin doses were communicated to the participants. HbA1c, proportion of BG readings in range (70-180 mg/dL, PIR), below range (<70 mg/dL, PBR) and above range (>180 mg/dL, PAR), and glycemic variability as the coefficient of variation (% CV) were measured at baseline, week 12, and week 24 and compared using repeated-measures analysis of variance (ANOVA) or Friedman's ANOVA. RESULTS: We recruited 40 people (55% women). Mean age was 57.9 years, BMI 27.8 kg/m2, and baseline HbA1c 9.8% (83.7 mmol/mol). Mean HbA1c improved by 1.7%, % CV reduced from 32.9% to 30.7%, PIR increased from 58.8% to 67.1% (all P <.01) by week 24, without any change in PBR. This was achieved with a 0.04 U/kg/d median increase in total daily dose of insulin and 0.9 kg weight gain over 24 weeks. CONCLUSION: Telemonitoring and titration of insulin using a connected glucose meter resulted in significant improvements in glycemia, characterized by a reduction in HbA1c, increase in PIR, and reduction in glycemic variability without any increase in hypoglycemia.

Rapid Desensitization for Insulin Allergy in Type 1 Diabetes Using an Insulin Pump: A Case Report and Literature Review.

OBJECTIVE: Insulin allergy, although uncommon, poses a significant challenge in those with type 1 diabetes mellitus (T1D) as insulin replacement is a necessity. Our objective is to describe a patient in whom rapid desensitization to insulin aspart was achieved using an insulin pump. METHODS: A 40-year-old woman with newly diagnosed T1D developed pruritic wheals over the abdomen after being injected with insulin glargine U-300 (Toujeo) and insulin aspart. Type 1 insulin hypersensitivity was confirmed through intradermal testing and positive insulin-specific immunoglobulin E levels. RESULT: The patient underwent rapid desensitization with an insulin pump. Half the anticipated daily basal requirement was initially subcutaneously administered before initiating low-dose insulin via the pump (0.000025 units/h) and increasing the dose every 30 minutes to reach her basal requirements within 5 hours. Subsequent larger bolus insulin doses did not produce any local or anaphylactic reactions. No pretreatment with corticosteroids or antihistamines was provided. CONCLUSION: Previous protocols for insulin desensitization span over days and often involve routine premedication. The case we presented suggests that insulin desensitization can be achieved over several hours using an insulin pump. A subcutaneous basal insulin cover should be provided prior to desensitization to avoid hyperglycemia necessitating an insulin bolus. Routine premedication may not always be necessary depending on reaction severity.

Progressive endoplasmic reticulum stress over time due to human insulin gene mutation contributes to pancreatic beta cell dysfunction.

AIMS/HYPOTHESIS: We studied the effects of heterozygous human INS gene mutations on insulin secretion, endoplasmic reticulum (ER) stress and other mechanisms in both MIN6 and human induced pluripotent stem cells (hiPSC)-derived beta-like cells, as well as the effects of prolonged overexpression of mutant human INS in MIN6 cells. METHODS: We modelled the structure of mutant C109Y and G32V proinsulin computationally to examine the in silico effects. We then overexpressed either wild-type (WT), mutant (C109Y or G32V), or both WT and mutant human preproinsulin in MIN6 cells, both transiently and stably over several weeks. We measured the levels of human and rodent insulin secreted, and examined the transcript and protein levels of several ER stress and apoptotic markers. We also reprogrammed human donor fibroblasts heterozygous for the C109Y mutation into hiPSCs and differentiated these into pancreatic beta-like cells, which were subjected to single-cell RNA-sequencing and transcript and protein analyses for ER stress and apoptotic markers. RESULTS: The computational modelling studies, and short-term and long-term expression studies in beta cells, revealed the presence of ER stress, organelle changes and insulin processing defects, resulting in a decreased amount of insulin secreted but not the ability to secrete insulin. By 9 weeks of expression of mutant human INS, dominant-negative effects of mutant INS were evident and beta cell insulin secretory capacity declined. INS+/C109Y patient-derived beta-like cells and single-cell RNA-sequencing analyses then revealed compensatory upregulation in genes involved in insulin secretion, processing and inflammatory response. CONCLUSIONS/INTERPRETATION: The results provide deeper insights into the mechanisms of beta cell failure during INS mutation-mediated diabetes disease progression. Decreasing spliced X-box binding protein 1 (sXBP1) or inflammatory response could be avenues to restore the function of the remaining WT INS allele.

Hypertriglyceridemia-induced pancreatitis in pregnancy: case review on the role of therapeutic plasma exchange.

SUMMARY: Gestational hypertriglyceridemia-induced pancreatitis is associated with significant maternal and fetal morbidity and mortality. We report a case of gestational hypertriglyceridemia-induced pancreatitis in a primigravida at 31-weeks gestation, complicated by impending preterm labor and metabolic acidosis requiring hemodialysis. This was successfully managed with therapeutic plasma exchange (TPE), followed by i.v. insulin, low-fat diet, and omega-3. Triglyceride levels stabilized after TPE and the patient underwent an uncomplicated term delivery. In pregnancy, elevated estrogen and insulin resistance exacerbate hypertriglyceridemia. Management is challenging as risks and benefits of treatment options need to be weighed against fetal wellbeing. We discuss management options including a review of previous case reports detailing TPE use, dietary optimization, and delivery timing. This case emphasizes the importance of multidisciplinary care to optimize maternal and fetal outcomes. LEARNING POINTS: Gestational hypertriglyceridemia-induced pancreatitis has high morbidity. A multidisciplinary team approach is a key as maternal and fetal needs must be addressed. Rapid lowering of triglycerides is crucial and can be achieved successfully and safely with plasma exchange. A low-fat diet while ensuring adequate nutrition in pregnancy is important. Timing of delivery requires consideration of fetal maturity and risk of recurrent pancreatitis.

When a storm showers the blood clots: a case of thyroid storm with systemic thromboembolism.

SUMMARY: Thyroid storm is a rare but potentially life-threatening complication of excessive thyroid hormone action. It is associated with a hypercoagulable state and reported to increase the risk of thromboembolism. However, the role of anticoagulation in thyroid storm still remains controversial and inconclusive. A 22-year-old male with no significant past medical history presented with acute severe generalised abdominal pain. He was found to be profoundly thyrotoxic on arrival at our institution and subsequently diagnosed with thyroid storm secondary to newly diagnosed Graves' disease. Extensive thromboses of the splanchnic, iliac, femoral veins and pulmonary arteries were subsequently demonstrated on CT scan. He had prolonged bowel ileus as a sequela of mesenteric ischaemia requiring total parenteral nutrition and non-oral forms of anti-thyroid drugs for management of hyperthyroidism. He was in sinus rhythm throughout his inpatient stay, and there was no personal history of prothrombotic conditions. His thrombophilia screen was normal. He eventually required jejunectomy due to jejunal ischaemia from extensive involvement of portal and mesenteric veins. He underwent radioiodine ablation for definitive treatment. He is currently hypothyroid and receiving thyroxine replacement. Thyroid storms are hypercoagulable states and can be associated with extensive thromboembolism even in the absence of atrial fibrillation. To our knowledge, this is the first report of severe extensive thromboembolism complicated by severe mesenteric ischaemia and bowel ileus in the setting of a thyroid storm. Routine prophylactic anticoagulation should be considered in those presenting with thyroid storms. LEARNING POINTS: Prolonged use of rectal propylthiouracil (PTU) for managing hyperthyroidism was effective in a patient who cannot take oral anti-thyroid drugs. Hyperthyroidism is a hypercoagulable state due to an imbalance between coagulation and fibrinolytic factors. Thyroid storm can be associated with extensive thromboembolism even in the absence of atrial fibrillation; routine prophylactic anticoagulation should be considered in the setting of thyroid storms.

Persistent Anxiety Is Associated with Higher Glycemia Post-Transition to Adult Services in Asian Young Adults with Diabetes.

BACKGROUND: There is little longitudinal information on psychological burden and metabolic outcomes in young adults with diabetes (YAD) in Asia. We aimed to evaluate the association between psychological status and glycemia at baseline and 2 years following transition in a cohort of YAD in Singapore. METHODS: Subjects with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), aged 17 to 25 years, were recruited from the YAD clinic in Singapore General Hospital. The Hospital Anxiety and Depression and Problem Areas for Diabetes scales were administered at transition (baseline) and at 18 to 24 months. Glycosylated hemoglobin (HbA1c) assessed during routine visits was tracked longitudinally. RESULTS: A total of 98 T1DM (74.8%) and 33 T2DM (25.2%) subjects were recruited between January 2011 and November 2017. At baseline, mean HbA1c was 8.6%±1.7%. Only 26.0% achieved HbA1c of ≤7.5% and 16.8% achieved HbA1c of <7%. At baseline, prevalence of anxiety was 29.8%. At 24 months, 14.1% had persistent anxiety. Those with persistent anxiety had the highest mean HbA1c, particularly at 6 months (persistently anxious vs. persistently non-anxious: 9.9%±1.2% vs. 8.2%±1.9%, P=0.009). At baseline, 9.2% of subjects had depression. This group also had poorer glycemia at baseline (HbA1c of depressed vs non-depressed: 9.6%±2.1% vs. 8.5%±1.6%, P=0.04), which persisted up to 24 months. CONCLUSION: The majority of YAD in Singapore have suboptimal glycemia. Psychological distress is a critical harbinger of poorer metabolic outcomes.

TRIal to slow the Progression Of Diabetes (TRIPOD): study protocol for a randomized controlled trial using wireless technology and incentives.

BACKGROUND: The outcomes for those with type 2 diabetes mellitus (T2DM) in Singapore are poor. In this TRIal to slow the Progression Of Diabetes (TRIPOD), we will evaluate the effectiveness and cost-effectiveness of a comprehensive diabetes management package (DMP), with or without a financial incentives program, M-POWER Rewards, in efforts to improve HbA1c levels for individuals with T2DM. METHODS/DESIGN: TRIPOD is a randomized, open-label, controlled, multi-center, superiority trial with three parallel arms: (1) usual care only, (2) usual care with DMP, and (3) usual care with DMP plus M-POWER Rewards. A total of 339 adults with sub-optimally controlled T2DM (self-reported HbA1c 7.5-11.0%) will be block randomized according to a 1:1:1 allocation ratio to the three arms. The primary outcome is mean change in HbA1c level at Month 12 from baseline. Secondary outcomes include mean change in HbA1c level at Months 6, 18, and 24; mean changes at Months 6, 12, 18, and 24 in weight, blood pressure, and self-reported physical activity, weight monitoring, blood glucose monitoring, medication adherence, diabetes self-management, sleep quality, work productivity and daily activity impairment, and health utility index; and proportion of participants initiating insulin treatment by Months 6, 12, 18, and 24. Incremental cost-effectiveness ratios will be computed based on costs per improvement in HbA1c at Month 12 and converted to cost per quality-adjusted life year gained. DISCUSSION: The TRIPOD study will present insights about the long-term cost-effectiveness and financial viability of the interventions and the potential for integrating within usual care. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03800680. Registered on 11 January 2019.

Psychometric validation of the Hypoglycemia Fear Survey-II (HFS-II) in Singapore.

OBJECTIVE: We conducted a cross-sectional study to adapt and validate the Hypoglycemia Fear Survey-II (HFS-II) for use in Singapore among persons with type 1 and 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: A total of 144 patients with type 1 or 2 diabetes on insulin therapy for at least a year completed the HFS-II between September and December 2013 in the Diabetes Center at Singapore General Hospital. We examined the validity (content, concurrent and discriminant validity, and construct validity) and reliability (internal consistency and test-retest reliability) of the instrument. Content validity was established using cognitive interviews. Construct validity was assessed using confirmatory factor analysis (CFA) followed by exploratory factor analysis (EFA) after the hypothesized two-factor structure was not confirmed by CFA. Measures of anxiety (Generalized Anxiety Disorder-7 (GAD-7)) and depression (Patient Health Questionnaire-9 (PHQ-9)) were used to establish concurrent validity; history of severe hypoglycemia and status of glycemic control were used to establish discriminant validity. Internal consistency was measured by Cronbach's α; test-retest reliability was measured by intracluster correlation coefficient (ICC). RESULTS: Scores of the adapted HFS-II had moderate positive correlations with measures of anxiety and depression scores (ranxiety=0.41, p<0.01; rdepression=0.37, p<0.01). Patients with a recent history of severe hypoglycemia had higher HFS-II scores than those without (mean difference=9, p<0.01). Patients with poor glycemic control had higher HFS-II scores than those with good control (p<0.05). The original two-factor structure was not confirmed in our sample. EFA results suggested a three-factor solution with the original Behavior subscale splitting into two dimensions. The adapted HFS-II displayed good internal consistency (Cronbach's α=0.93) and test-retest reliability (ICC=0.75). CONCLUSIONS: The adapted HFS-II has good content, concurrent and discriminant validity, and reliability, but its constructvalidity was not proven with the Behavior subscale turning out to be non-unidimensional.

Incremental cost-effectiveness of algorithm-driven genetic testing versus no testing for Maturity Onset Diabetes of the Young (MODY) in Singapore.

BACKGROUND: Offering genetic testing for Maturity Onset Diabetes of the Young (MODY) to all young patients with type 2 diabetes has been shown to be not cost-effective. This study tests whether a novel algorithm-driven genetic testing strategy for MODY is incrementally cost-effective relative to the setting of no testing. METHODS: A decision tree was constructed to estimate the costs and effectiveness of the algorithm-driven MODY testing strategy and a strategy of no genetic testing over a 30-year time horizon from a payer's perspective. The algorithm uses glutamic acid decarboxylase (GAD) antibody testing (negative antibodies), age of onset of diabetes (<45 years) and body mass index (<25 kg/m2 if diagnosed >30 years) to stratify the population of patients with diabetes into three subgroups, and testing for MODY only among the subgroup most likely to have the mutation. Singapore-specific costs and prevalence of MODY obtained from local studies and utility values sourced from the literature are used to populate the model. RESULTS: The algorithm-driven MODY testing strategy has an incremental cost-effectiveness ratio of US$93 663 per quality-adjusted life year relative to the no testing strategy. If the price of genetic testing falls from US$1050 to US$530 (a 50% decrease), it will become cost-effective. CONCLUSION: Our proposed algorithm-driven testing strategy for MODY is not yet cost-effective based on established benchmarks. However, as genetic testing prices continue to fall, this strategy is likely to become cost-effective in the near future.