Aparna Pal

The genetics of type 2 diabetes and its clinical relevance

The increasing worldwide prevalence of type 2 diabetes (T2D) motivates efforts to use genetics to define key pathways involved in disease predisposition, and thereby to improve management of the disease. Research over the past 5 years has taken the total number of genetic loci implicated in T2D susceptibility beyond 60, and the emphasis is now shifting to the translation of these genetic insights into clinical value. Clinical translation may flow from the identification of novel therapeutic targets, but opportunities also exist with respect to individual prediction, diagnostic biomarkers and therapeutic optimization. To date, the main clinical impact has been seen for relatively rare, monogenic forms of diabetes rather than common T2D. However, the advent of high throughput sequencing approaches may herald discovery of rare and low frequency variants that offer greater translational potential.

Evaluation of Serum 1,5 Anhydroglucitol Levels as a Clinical Test to Differentiate Subtypes of Diabetes

OBJECTIVE Assignment of the correct molecular diagnosis in diabetes is necessary for informed decisions regarding treatment and prognosis. Better clinical markers would facilitate discrimination and prioritization for genetic testing between diabetes subtypes. Serum 1,5 anhydroglucitol (1,5AG) levels were reported to differentiate maturity-onset diabetes of the young due to HNF1A mutations (HNF1A-MODY) from type 2 diabetes, but this requires further validation. We evaluated serum 1,5AG in a range of diabetes subtypes as an adjunct for defining diabetes etiology. RESEARCH DESIGN AND METHODS 1,5AG was measured in U.K. subjects with: HNF1A-MODY (n = 23), MODY due to glucokinase mutations (GCK-MODY, n = 23), type 1 diabetes (n = 29), latent autoimmune diabetes in adults (LADA, n = 42), and type 2 diabetes (n = 206). Receiver operating characteristic curve analysis was performed to assess discriminative accuracy of 1,5AG for diabetes etiology. RESULTS Mean (SD range) 1,5AG levels were: GCK-MODY 13.06 μg/ml (5.74–29.74), HNF1A-MODY 4.23 μg/ml (2.12–8.44), type 1 diabetes 3.09 μg/ml (1.45–6.57), LADA 3.46 μg/ml (1.42–8.45), and type 2 diabetes 5.43 (2.12–13.23). Levels in GCK-MODY were higher than in other groups (P < 10−4 vs. each group). HNF1A-MODY subjects showed no difference in unadjusted 1,5AG levels from type 2 diabetes, type 1 diabetes, and LADA. Adjusting for A1C revealed a difference between HNF1A-MODY and type 2 diabetes (P = 0.001). The discriminative accuracy of unadjusted 1,5AG levels was 0.79 for GCK-MODY versus type 2 diabetes and 0.86 for GCK-MODY versus HNF1A-MODY but was only 0.60 for HNF1A-MODY versus type 2 diabetes. CONCLUSIONS In our dataset, serum 1,5AG performed well in discriminating GCK-MODY from other diabetes subtypes, particularly HNF1A-MODY. Measurement of 1,5AG levels could inform decisions regarding MODY diagnostic testing.

Loss-of-Function Mutations in the Cell-Cycle Control Gene CDKN2A Impact on Glucose Homeostasis in Humans

At the CDKN2A/B locus, three independent signals for type 2 diabetes risk are located in a noncoding region near CDKN2A. The disease-associated alleles have been implicated in reduced β-cell function, but the underlying mechanism remains elusive. In mice, β-cell–specific loss of Cdkn2a causes hyperplasia, while overexpression leads to diabetes, highlighting CDKN2A as a candidate effector transcript. Rare CDKN2A loss-of-function mutations are a cause of familial melanoma and offer the opportunity to determine the impact of CDKN2A haploinsufficiency on glucose homeostasis in humans. To test the hypothesis that such individuals have improved β-cell function, we performed oral and intravenous glucose tolerance tests on mutation carriers and matched control subjects. Compared with control subjects, carriers displayed increased insulin secretion, impaired insulin sensitivity, and reduced hepatic insulin clearance. These results are consistent with a model whereby CDKN2A loss affects a range of different tissues, including pancreatic β-cells and liver. To test for direct effects of CDKN2A-loss on β-cell function, we performed knockdown in a human β-cell line, EndoC-bH1. This revealed increased insulin secretion independent of proliferation. Overall, we demonstrated that CDKN2A is an important regulator of glucose homeostasis in humans, thus supporting its candidacy as an effector transcript for type 2 diabetes–associated alleles in the region.

Routine genetic screening with a multi-gene panel in patients with pheochromocytomas

PurposeSeveral new gene mutations have been reported in recent years to be associated with a risk of familial pheochromocytoma. However, it is unclear as to whether extensive genetic testing is required in all patients.MethodsThe clinical data of consecutive patients operated for pheochromocytoma over a decade in a tertiary referral center were reviewed. Genetic screening was performed using a 10-gene panel: RET, VHL, SDHB, SDHD, SDHA, SDHC, SDHAF2, MAX, TMEM127 and FH.ResultsA total of 166 patients were analyzed: 87 of them had genetic screening performed (39 M: 44.8%, 48 F: 55.2%, age range 6–81 years, mean 45±16.8 years). In total, 22/87 (25.3%) patients had germline mutations, while 65/87 (74.7%) patients presented with apparently sporadic tumors. Germline VHL mutations were identified in 11.7% of patients, RET in 6.8% (five MEN2A/MEN2 and one MEN2B/MEN3), SDHD in 2.3%, MAX in 2.3%, SDHB in 1.1%, and TMEM127 in 1.1% of patients. At diagnosis, 15.1% of patients with unilateral non-syndromic pheochromocytoma showed germline mutations. We identified 19.7% of mutations in patients with unilateral-non-recurrent pheochromocytomas within 5 years vs. 50% in the recurrent-bilateral-metastatic group (p = 0.01). Germline mutations were more frequently seen with bilateral pheochromocytomas (p = 0.001): 80% of patients with bilateral disease had germline mutations (4 VHL, 3 RET, 1 MAX).ConclusionsThe advent of rapid genetic screening using a gene-panel makes it feasible to screen large cohorts of patients and provides a valuable tool to contribute to the prediction of bilateral and malignant disease and to screen family members.

PTEN mutations as a cause of constitutive insulin sensitivity and obesity in human beings

Abstract Background Epidemiological evidence and genetic evidence link type 2 diabetes, obesity, and cancer. The tumour suppressor phosphatase and tensin homolog (PTEN) has roles in both cellular growth and metabolic signalling. Germline PTEN mutations cause Cowden syndrome, a cancer predisposition syndrome, providing an opportunity to study the metabolic effects of PTEN haploinsufficiency in human beings. We investigated insulin sensitivity and beta-cell function in patients with Cowden syndrome. Methods Insulin sensitivity and beta-cell function were assessed in 15 carriers of the PTEN mutation and 15 matched controls by oral glucose tolerance tests and hyperinsulinaemic euglycaemic clamps. Insulin signalling was measured in biopsies of muscle and adipose tissue with immunoblot. The effect of PTEN haploinsufficiency on obesity was assessed with anthropometric indices, dual-emission x-ray absorptiometry, and skinfold thickness in patients and controls. Findings All measures of insulin resistance were lower in mutation carriers, including fasting plasma insulin (mean 29 pmol/L [range 9–99] vs 74 [22–185], p=0·001). This was confirmed by hyperinsulinaemic euglycaemic clamps, which showed glucose infusion rates twice as high in patients as in controls (p=0·009). This higher insulin sensitivity was explained by enhanced insulin signalling through the PI3K-AKT pathway, evidenced by increased AKT phosphorylation in both muscle and adipose tissue. PTEN mutation carriers were obese compared with population-based controls (mean BMI 32 kg/m 2 [range 23–42] vs 26 [15–48], p Interpretation PTEN haploinsufficiency is the first description of a monogenic cause of profound insulin sensitivity. The constitutive insulin sensitisation is apparently obesogenic. This study demonstrates a potential divergent effect on diabetes and cancer risk, with PTEN mutations increasing risk of obesity and cancer but decreasing risk of type 2 diabetes via enhanced insulin sensitivity. Funding UK Medical Research Council and Wellcome Trust.

Clinical, Endocrine and Imaging Characteristics of Patients with Primary Hypophysitis

Primary hypophysitis (PH) is a rare disease with a poorly-defined natural history. Our aim was to characterise patients with PH at presentation and during prolonged follow-up. Observational retrospective study of 22 patients was conducted from 3 centres. In 14 patients, PH was confirmed histologically and in the remaining 8 clinically, after excluding secondary causes of hypophysitis. All patients had hormonal and imaging investigations before any treatment. Median follow up was 48 months (25-75%: 3-60). There was a female predominance with a female/male ratio: 3.4:1. Eight out of 22 patients had another autoimmune disease. Headaches and gonadal dysfunction were the most common symptoms. Five patients presented with panhypopituitarism; 17 patients had anterior pituitary deficiency, and 7 had diabetes insipidus. At presentation, 9 patients were treated surgically, 5 received replacement hormonal treatment, and 8 high-dose glucocorticoids from whom 5 in association with other immunosuppressive agents. Six patients showed complete recovery of pituitary hormonal deficiencies while 6 showed a partial recovery during a 5-year follow-up period. No difference was found between patients treated with surgery and those treated medically. The overall relapse rate was 18%. PH can be manifested with a broad spectrum of clinical and hormonal disturbances. Long-term follow-up is required to define the natural history of the disease and response to treatment, since pituitary hormonal recovery or relapse may appear many years after initial diagnosis. We suggest that surgery and immunosuppressive therapy be reserved for exceptional cases.

Local optometrists are a major source of referrals to a pituitary tumour clinic

Pituitary adenomas can be identified pathologically in some 20-25% of autopsy specimens, 12 but only around 1/1000 of the population have clinically significant tumours (Daly et al 13 2006, Fernandez et al 2010). As the tumour expands, the optic chiasm may be compressed 14 from below, causing visual field abnormalities including the classic bitemporal hemianopia. 15 These visual symptoms are the most common objective manifestations of non-functioning 16 pituitary adenomas, and demand urgent decompression to increase the probability of a 17 complete normalisation of visual function. Delayed diagnosis may lead to irreversible visual 18 loss, especially if the chiasmal compression is associated with more evident field defects 19 (Lee et al 2013) or has been of long duration (Dutta et al 2016), although improvement may 20 continue sometime after surgery (Harris et al 1989). In a multivariate analysis, only 21 preceding visual defect predicted the degree of recovery, although this could continue for at 22 least 5 years (Gnanalingham et al 2005). In general, it is anticipated that patients will 23 present to either their general practitioner or to an ophthalmologist complaining of visual 24 changes, but patients may undergo considerable visual loss without realisation of the 25 disorder. The onset of the visual deficit is usually gradual such that many patients might not 26 seek medical consultation for months or even years. Thus, early diagnosis is critical but may 27 be significantly delayed by a failure of concern by the patient or their clinicians. 28

Genetically Programmed Defects in β-Cell Function

A significant level of insight into the machinery and workings of the pancreatic β-cell originates from the study of naturally occurring mutations in genes that encode the various components. Identifying these mutations has been important not only for tailoring treatment towards the specific subtype of diabetes associated, but also for highlighting the importance and pivotal role of a number of elements along the pathway of glucose-stimulated insulin secretion within the pancreatic β-cell.

Strategic steps towards longer and reliable blast furnace trough campaign – Tata Steel experience

Abstract At Tata Steel, Jamshedpur works the hot metal production capacity was enhanced from 3·57 mT in 1997–1998 to 5·51 mT in 2007–2008 with the same number of cast houses, thereby, increasing the thermal load on the runner system. Maximising trough availability and ensuring zero breakouts were the means to fulfill the objective of handling the increased furnace production. Significant changes in trough refractory design and introduction of new materials like prefabricated shapes helped to improve reliability of the troughs. The paper presents the design and mode of operation of main troughs of different blast furnaces (BFs) operated at Jamshedpur works, modification of trough design in the upgraded G-BF and its performance and details of improvements made in the trough back-up refractory lining, its wear monitoring and cooling systems.

A rare case of SDHB mutation in a male individual with pituitary adenoma, and paraganglioma/phaeochromocytoma syndrome

The role of mutations in the genes encoding the succinate dehydrogenase (SDH) subunits, in tumorigenesis has been described previously and especially the predisposition to the development of the hereditary paraganglioma/phaeochromocytoma syndrome (HPGL/PCC). To our knowledge this may be the first reported case of a lung neuroendocrine tumour, phaeochromocytoma and pituitary macroadenoma on the background of a mutation in the SDHB gene. References