Preventing diabetes complications.

The key aim of diabetes management is to prevent complications, which are a major cause of morbidity and mortality. At an individual level, people with diabetes are less likely than they were several decades ago to experience classical macrovascular and microvascular complications as a result of improvements in modifiable cardiovascular risk factors and preventive healthcare. However, a significant burden of diabetes complications persists at a population level because of the increasing incidence of diabetes, as well as longer lifetime exposure to diabetes because of younger diagnosis and increased life expectancy. Trials have shown that the most effective strategy for preventing complications of diabetes is a multifactorial approach focussing simultaneously on the management of diet, exercise, glucose levels, blood pressure and lipids. In addition to the cornerstone strategies of addressing diet, exercise and lifestyle measures, the introduction of newer glucose-lowering agents, including sodium-glucose transport protein 2 inhibitors and glucagon-like peptide-1 agonists, have brought about a paradigm shift in preventing the onset and progression of complications of type 2 diabetes, particularly cardiovascular and renal disease. The improvement in rates of classical complications of diabetes over time has been accompanied by a growing awareness of non-traditional complications, including non-alcoholic fatty liver disease. These emerging complications may not respond to a glycaemic-centred approach alone and highlight the importance of foundational strategies centred on lifestyle measures and supported by pharmaceutical therapy to achieve weight loss and reduce metabolic risk in patients living with diabetes.

Does weight management after gestational diabetes mellitus diagnosis improve pregnancy outcomes? A multi-ethnic cohort study.

AIMS: To assess the impact of achieving an Institute of Medicine based personalised weight target in addition to conventional glycaemic management after gestational diabetes mellitus diagnosis on maternal and neonatal outcomes. METHODS: A retrospective audit of clinical data (2016-2019) for singleton gestational diabetes pregnancies was conducted in a multi-ethnic cohort. Logistic regression analyses assessed relationships between achieving, exceeding and gaining less than a personalised weight target provided after gestational diabetes diagnosis and rates of large for gestational age, small for gestational age infants, insulin therapy initiation and neonatal outcomes. Adjusted odds ratios (aOR) were adjusted for glucose 2-h post-glucose load value, family history of type 2 diabetes, previous gestational diabetes, macrosomia in a previous pregnancy, and East and South-East Asian ethnicity. RESULTS: Of 1034 women, 44% (n = 449) achieved their personalised weight target. Women who exceeded their personalised weight target had significantly and higher mean insulin doses (28.8 ± 21.5 units vs. 22.7 ± 18.7, p = 0.006) and higher rates of large for gestational age infants (19% vs. 9.8%, p < 0.001), with aOR of 1.99 [95% CI 1.25-3.15] p = 0.004, but no difference in rates of small for gestational age infants (5.3% vs. 8.0%) (aOR 0.77 [0.41-1.44] p = 0.41). Lower rates of large for gestational age infants occurred in those who gained below their personalised weight target (aOR 0.48 [0.25-0.95] p = 0.034), but rates of small for gestational age infants concurrently increased (aOR 1.9 [1.19-3.12] p = 0.008). CONCLUSIONS: Weight management after gestational diabetes diagnosis does not appear to be too late to confer additional benefits to glucose-lowering treatment, resulting in lower mean insulin doses, and lower rates of large for gestational age infants without increasing the risk of small for gestational age infants.

Are the Institute of Medicine weight gain targets applicable in women with gestational diabetes mellitus?

AIMS/HYPOTHESIS: Our aim was to study the relationship between excessive gestational weight gain (GWG) according to Institute of Medicine (IOM) targets and perinatal outcomes, and examine whether modifying targets may improve outcomes in women with gestational diabetes mellitus (GDM). METHODS: This was a retrospective cohort study of all GDM pregnancies from 1992 to 2013. ORs were calculated for associations between excessive GWG (EGWG) using IOM targets and adverse pregnancy outcomes. ORs were then adjusted for maternal age, gestational age at diagnosis, prepregnancy BMI, gravidity, parity, ethnicity, antenatal fasting blood glucose level (BGL), 2 h BGL and HbA1c. BMI was categorised into underweight (<18.5 kg/m2), healthy weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2) and obese (≥30 kg/m2). Large for gestational age (LGA) was defined as birthweight above the 90th percentile, small for gestational age (SGA) was birthweight below the 10th percentile, macrosomia was birthweight >4000 g, and preterm delivery was delivery prior to 37 weeks' gestation. Modified GWG targets were derived by: (1) subtracting 2 kg from the upper IOM target only; (2) subtracting 2 kg from both upper and lower targets; (3) using the interquartile range of maternal GWG of women with infants who were appropriate for gestational age per BMI category; and (4) restricting GWG to 0-4 kg in women with BMI ≥35 kg/m2. RESULTS: Among 3095 GDM pregnancies, only 31.7% had GWG within IOM guidelines. Adjusted ORs for women who exceeded GWG were Caesarean section (1.5; 95% CI 1.2, 1.9), LGA (1.8; 95% CI 1.4, 2.4) and macrosomia (2.3; 95% CI 1.6, 3.3); there was a lower risk of SGA (adjusted OR 0.5; 95% CI 0.3, 0.7). CONCLUSIONS/INTERPRETATION: EGWG according to IOM targets was associated with Caesarean section, LGA and macrosomia. Modification of IOM criteria, including more restrictive targets, did not improve perinatal outcomes.

A novel validated model for the prediction of insulin therapy initiation and adverse perinatal outcomes in women with gestational diabetes mellitus.

AIMS/HYPOTHESIS: Identifying women with gestational diabetes mellitus who are more likely to require insulin therapy vs medical nutrition therapy (MNT) alone would allow risk stratification and early triage to be incorporated into risk-based models of care. The aim of this study was to develop and validate a model to predict therapy type (MNT or MNT plus insulin [MNT+I]) for women with gestational diabetes mellitus (GDM). METHODS: Analysis was performed of de-identified prospectively collected data (1992-2015) from women diagnosed with GDM by criteria in place since 1991 and formally adopted and promulgated as part of the more detailed 1998 Australasian Diabetes in Pregnancy Society management guidelines. Clinically relevant variables predictive of insulin therapy by univariate analysis were dichotomised and included in a multivariable regression model. The model was tested in a separate clinic population. RESULTS: In 3317 women, seven dichotomised significant independent predictors of insulin therapy were maternal age >30 years, family history of diabetes, pre-pregnancy obesity (BMI ≥30 kg/m(2)), prior GDM, early diagnosis of GDM (<24 weeks gestation), fasting venous blood glucose level (≥5.3 mmol/l) and HbA1c at GDM diagnosis ≥5.5% (≥37 mmol/mol). The requirement for MNT+I could be estimated according to the number of predictors present: 85.7-93.1% of women with 6-7 predictors required MNT+I compared with 9.3-14.7% of women with 0-1 predictors. This model predicted the likelihood of several adverse outcomes, including Caesarean delivery, early delivery, large for gestational age and an abnormal postpartum OGTT. The model was validated in a separate clinic population. CONCLUSIONS/INTERPRETATION: This validated model has been shown to predict therapy type and the likelihood of several adverse perinatal outcomes in women with GDM.

Fulminant type 1 diabetes mellitus in a GDM pregnancy: early recognition is vital for maternal and fetal outcomes.

Summary: Fulminant type 1 diabetes mellitus (FT1DM) is characterised by extremely rapid destruction of pancreatic beta cells. An association between FT1DM and pregnancy has been reported and can lead to unfavourable pregnancy outcomes without timely treatment. We report a case of FT1DM in a pregnancy with gestational diabetes mellitus (GDM), the first of its kind in the English literature to date. A 27-year-old woman with insulin-requiring GDM presented with rapidly deteriorating glycaemic control in her third trimester of pregnancy despite good concordance to treatment. The investigation identified the hallmarks of FT1DM: hyperglycaemia with acute metabolic decompensation and non-immune-mediated beta-cell failure. She received prompt treatment with intravenous insulin therapy and was transitioned to subcutaneous insulin once biochemical improvement had been achieved, albeit with higher insulin requirements than before. She had a good pregnancy outcome and delivered a healthy male infant 5 weeks later through induction of labour. Due to persistent beta-cell dysfunction, she remained on basal-bolus insulin postpartum. This case highlights the importance of early recognition and treatment of FT1DM in pregnancy to prevent adverse maternal and fetal prognoses. Learning points: Fulminant type 1 diabetes mellitus (FT1DM) is a subtype of type 1 diabetes characterised by extremely rapid beta-cell destruction, leading to abrupt-onset hyperglycaemia with ketosis or ketoacidosis. The pathognomonic characteristics of FT1DM include the development of diabetic ketosis or ketoacidosis typically within 7 days after the onset of symptoms of hyperglycaemia, a near-normal level of glycated haemoglobin despite elevated plasma glucose levels and the absence of islet cell autoantibodies. The pathophysiology of FT1DM is unclear but the association with genetic predisposition, viral infection and pregnancy has been reported. Due to its predilection for pregnancy, clinicians should have a high index of suspicion for FT1DM in pregnant women with rapidly progressing hyperglycaemic ketoacidosis. As diabetic ketoacidosis in pregnancy is associated with adverse maternal and fetal outcomes, immediate initiation of treatment in pregnant women with suspected FT1DM is extremely vital to prevent morbidity and mortality, even if investigations are still underway. Patients with FT1DM require lifelong insulin therapy due to the complete loss of beta-cell function.

MEN4, the MEN1 Mimicker: A Case Series of three Phenotypically Heterogenous Patients With Unique CDKN1B Mutations.

CONTEXT: Germline CDKN1B pathogenic variants result in multiple endocrine neoplasia type 4 (MEN4), an autosomal dominant hereditary tumor syndrome variably associated with primary hyperparathyroidism, pituitary adenoma, and duodenopancreatic neuroendocrine tumors. OBJECTIVE: To report the phenotype of 3 unrelated cases each with a unique germline CDKN1B variant (of which 2 are novel) and compare these cases with those described in the current literature. DESIGN/METHODS: Three case studies, including clinical presentation, germline, and tumor genetic analysis and family history. SETTING: Two tertiary University Hospitals in Sydney, New South Wales, and 1 tertiary University Hospital in Canberra, Australian Capital Territory, Australia. OUTCOME: Phenotype of the 3 cases and their kindred; molecular analysis and tumor p27kip1 immunohistochemistry. RESULTS: Family A: The proband developed multiglandular primary hyperparathyroidism, a microprolactinoma and a multifocal nonfunctioning duodenopancreatic neuroendocrine tumor. Family B: The proband was diagnosed with primary hyperparathyroidism from a single parathyroid adenoma. Family C: The proband was diagnosed with a nonfunctioning pituitary microadenoma and ectopic Cushing's syndrome from an atypical thymic carcinoid tumor. Germline sequencing in each patient identified a unique variant in CDKN1B, 2 of which are novel (c.179G > A, p.Trp60*; c.475G > A, p.Asp159Asn) and 1 previously reported (c.374_375delCT, p.Ser125*). CONCLUSIONS: Germline CDKN1B pathogenic variants cause the syndrome MEN4. The phenotype resulting from the 3 pathogenic variants described in this series highlights the heterogenous nature of this syndrome, ranging from isolated primary hyperparathyroidism to the full spectrum of endocrine manifestations. We report the first described cases of a prolactinoma and an atypical thymic carcinoid tumor in MEN4.

Longest survival with primary intracranial malignant melanoma: A case report and literature review.

BACKGROUND: Primary intracranial malignant melanoma (PIMM) is rare, and its prognosis is very poor. It is not clear what systematic treatment strategy can achieve long-term survival. This case study attempted to identify the optimal strategy for long-term survival outcomes by reviewing the PIMM patient with the longest survival following comprehensive treatment and by reviewing the related literature. CASE SUMMARY: The patient is a 47-year-old Chinese man who suffered from dizziness and gait disturbance. He underwent surgery for right cerebellum melanoma and was subsequently diagnosed by pathology in June 2000. After the surgery, the patient received three cycles of chemotherapy but relapsed locally within 4 mo. Following the second surgery for total tumor resection, the patient received an injection of Newcastle disease virus-modified tumor vaccine, interferon, and ß-elemene treatment. The patient was tumor-free with a normal life for 21 years before the onset of the recurrence of melanoma without any symptoms in July 2021. A third gross-total resection with adjuvant radiotherapy and temozolomide therapy was performed. Brain magnetic resonance imaging showed no residual tumor or recurrence 3 mo after the 3rd operation, and the patient recovered well without neurological dysfunction until the last follow-up in June 2022, which was 22 years following the initial treatment. CONCLUSION: It is important for patients with PIMM to receive comprehensive treatment to enable the application of the most appropriate treatment strategies. Long-term survival is not impossible in patients with these malignancies.

Hypophosphataemic osteomalacia in patients on adefovir dipivoxil.

Fanconi syndrome results from generalised renal tubular toxicity and, owing to phosphate wasting can cause hypophosphataemic osteomalacia. Large clinical trials advocated the safety of adefovir dipivoxil at a daily dose of 10 mg, the standard dose given to patients with hepatitis B. We diagnosed Fanconi syndrome in conjunction with severe osteomalacia in 2 hepatitis B-positive patients on standard-dose adefovir therapy. The first patient was a 40-year-old male with a 5 month history of bone pain involving his knees, ankles, and ribs. He had been receiving adefovir dipivoxil for 27 months before the development of hypophosphataemia, urinary phosphate wasting, and aminoaciduria. These abnormalities resolved within weeks of discontinuation of adefovir dipivoxil and supplementation with elemental phosphate, calcium carbonate, and cholecalciferol. The second patient was a 53-year-old female with a 6 month history of lethargy, cachexia, and generalized bone pain. She had been receiving adefovir for 64 months before the development of these symptoms. She had hypophosphataemia, hypocalcaemia, metabolic acidosis, and severe vitamin D deficiency, but initially no urinary phosphate wasting. Four months of high-dose cholecalciferol supplementation unmasked her Fanconi syndrome including significant urinary phosphate wasting. The patient improved within weeks of discontinuation of adefovir and supplementation with elemental phosphate, calcium carbonate, and calcitriol. Despite large clinical trials advocating the safety of adefovir dipivoxil at 10-mg daily, long-term use of this agent may be nephrotoxic and in rare cases, cause Fanconi syndrome and severe hypophosphataemic osteomalacia. Clinicians prescribing this drug should be aware of this potential complication.

Excessive Weight Gain Before and During Gestational Diabetes Mellitus Management: What Is the Impact?

OBJECTIVE: Conventional gestational diabetes mellitus (GDM) management focuses on managing blood glucose in order to prevent adverse outcomes. We hypothesized that excessive weight gain at first presentation with GDM (excessive gestational weight gain [EGWG]) and continued EGWG (cEGWG) after commencing GDM management would increase the risk of adverse outcomes, despite treatment to optimize glycemia. RESEARCH DESIGN AND METHODS: Data collected prospectively from pregnant women with GDM at a single institution were analyzed. GDM was diagnosed on the basis of Australasian Diabetes in Pregnancy Society 1998 guidelines (1992-2015). EGWG means having exceeded the upper limit of the Institute of Medicine-recommended target ranges for the entire pregnancy, by GDM presentation. The relationship between EGWG and antenatal 75-g oral glucose tolerance test (oGTT) values and adverse outcomes was evaluated. Relationships were examined between cEGWG, insulin requirements, and large-for-gestational-age (LGA) infants. RESULTS: Of 3,281 pregnant women, 776 (23.6%) had EGWG. Women with EGWG had higher mean fasting plasma glucose (FPG) on oGTT (5.2 mmol/L [95% CI 5.1-5.3] vs. 5.0 mmol/L [95% CI 4.9-5.0]; P < 0.01), after adjusting for confounders, and more often received insulin therapy (47.0% vs. 33.6%; P < 0.0001), with an adjusted odds ratio (aOR) of 1.4 (95% CI 1.1-1.7; P < 0.01). aORs for each 2-kg increment of cEGWG were a 1.3-fold higher use of insulin therapy (95% CI 1.1-1.5; P < 0.001), an 8-unit increase in final daily insulin dose (95% CI 5.4-11.0; P < 0.0001), and a 1.4-fold increase in the rate of delivery of LGA infants (95% CI 1.2-1.7; P < 0.0001). CONCLUSIONS: The absence of EGWG and restricting cEGWG in GDM have a mitigating effect on oGTT-based FPG, the risk of having an LGA infant, and insulin requirements.

The role of insulin glulisine to improve glycemic control in children with diabetes mellitus.

Glulisine (Apidra(®)) is a rapid-acting human insulin analog approved for use in children with diabetes mellitus ≥4 years of age. Management of children with type 1 diabetes has seen a shift in favor of mimicking normal physiological insulin responses with multiple daily injections or continuous subcutaneous insulin infusions (CSII). Few studies have compared the rapid-acting insulin analogs in this population but limited data indicate that glulisine is as effective as lispro when used in a basal-bolus regimen. This review appraises the current available studies and reviews on insulin glulisine in children. An extensive keyword search of 'insulin glulisine', 'insulin analogs', and 'Apidra' in the pediatric population was performed. These studies have suggested that glulisine is safe, well tolerated, and is an effective option in the diabetes armamentarium. Further studies are needed to determine its safety for use in CSII pumps in the pediatric population.

A new quantitative LC tandem mass spectrometry assay for serum 25-hydroxy vitamin D.

BACKGROUND: The accurate measurement of 25-hydoxy vitamin D (25OH-D) in serum has been a challenge for many years. We developed a liquid chromatography tandem mass spectrometry (LC Tandem MS) assay for the quantitative determination of 25OH-D(2) and 25OH-D(3) in serum. The new method was compared with two widely used commercially available immunoassays. METHODS: Sample preparation involved protein precipitation with acetonitrile containing deuterated forms of the target species as internal standards. An API 5000 mass spectrometer coupled with a photoionization source was used for quantitation. The performance of the new LC Tandem MS assay was compared with a radioimmunoassay (RIA, Diasorin) and a chemiluminescence immunoassay (ECLIA, Roche Diagnostics), analysing serum obtained from 152 individuals. RESULTS: Using 100 µl of serum, the LC Tandem MS assay had a limit of quantitation of 1.3 nmol/L for both 25OH-D(2) and 25OH-D(3) with a linear response between 1.3 and 625 nmol/L and accuracy of between 95 and 124%. Intra- and inter-assay precision were ≤7% and ≤4%, respectively. Measurement of 25OH-D levels in 152 serum samples gave run averages of 71, 56 and 62 nmol/L for LC Tandem MS, ECLIA and RIA, respectively. Correlations between the various methods were: LC Tandem MS vs. RIA: r=0.931; LC Tandem MS vs. ECLIA: r=0.784; RIA vs. ECLIA: r=0.787. The LC Tandem MS method had a positive proportional bias of 26% over the RIA, whereas the ECLIA showed variable differences. CONCLUSION: The new LC Tandem MS assay is accurate and precise at physiologically relevant 25OH-D concentrations, and compares favourably with the RIA. In contrast, the ECLIA shows variable bias with the other assays tested.