INS gene mutations
May 9, 2012
Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood.
Edghill E.L., Flanagan S.E., Patch A.M., Boustred C., Parrish A., Shields B., Shepherd M.H., Hussain K., Kapoor R.R., Malecki M., MacDonald M.J., Stoy J., Steiner D.F., Philipson L.H., Bell G.I., Hattersley A.T., Ellard S.
OBJECTIVE: Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes (PND). We aimed to determine the prevalence, genetics, and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood, or adulthood. RESEARCH DESIGN AND METHODS: The INS gene was sequenced in 285 patients with diabetes diagnosed before 2 years of age, 296 probands with maturity-onset diabetes of the young (MODY), and 463 patients with young-onset type 2 diabetes (nonobese, diagnosed <45 years). None had a molecular genetic diagnosis of monogenic diabetes. RESULTS: We identified heterozygous INS mutations in 33 of 141 probands diagnosed at <6 months, 2 of 86 between 6 and 12 months, and none of 58 between 12 and 24 months of age. Three known mutations (A24D, F48C, and R89C) account for 46% of cases. There were six novel mutations: H29D, L35P, G84R, C96S, S101C, and Y103C. INS mutation carriers were all insulin treated from diagnosis and were diagnosed later than ATP-sensitive K(+) channel mutation carriers (11 vs. 8 weeks, P < 0.01). In 279 patients with PND, the frequency of KCNJ11, ABCC8, and INS gene mutations was 31, 10, and 12%, respectively. A heterozygous R6C mutation cosegregated with diabetes in a MODY family and is probably pathogenic, but the L68M substitution identified in a patient with young-onset type 2 diabetes may be a rare nonfunctional variant. CONCLUSIONS: We conclude that INS mutations are the second most common cause of PND and a rare cause of MODY. Insulin gene mutation screening is recommended for all diabetic patients diagnosed before 1 year of age.
Clinical impact of hyperproinsulinemia
May 9, 2012
Hyperproinsulinemia and Proinsulin-to-Insulin Ratios in Swedish Middle-aged Men: Association with Glycemia and Insulin Resistance but Not with Family History of Diabetes
- V. Grill 1 , ,2 ,
- B. Dinesen 3 ,
- S. Carlsson 4 ,
- S. Efendic 1 ,
- O. Pedersen 3 and
- C.-G. Östenson 1
+ Author Affiliations
1Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
2Department of Medicine, Endocrinology Section, University Hospital of Trondheim, Trondheim, Norway.
3Steno Diabetes Center, Gentofte, Denmark.
4Division of Epidemiology, Karolinska University Hospital, Stockholm, Sweden.
- Received November 14, 2000.
- Accepted January 11, 2002.
- http://aje.oxfordjournals.org/content/155/9/834.full
Abstract
Elevated proinsulin and proinsulin/insulin ratios are features of abnormal β-cell function in type 2 diabetes. The participation of genetic factors is disputed. The authors wished to investigate relations between family history of diabetes on one hand and proinsulin as well as proinsulin/immunoreactive insulin ratios on the other. A large, population-based sample of Swedish men aged 35–54 years in 1992 was studied. Subjects without known diabetes were selected either to have a strong family history of diabetes (n = 1,619) or no history of the disease (n = 1,495). An oral glucose tolerance test detected 172 subjects with impaired glucose tolerance and 55 subjects with previously unknown diabetes according to World Health Organization 1985 criteria. In multiple regression analysis, fasting levels of proinsulin and proinsulin/insulin ratios were positively associated both with the 2-hour glucose level (as a continuous variable) and with obesity, whereas a negative association was found with birth weight. No association was found with family history of diabetes or with chronologic age. These findings indicate that elevated proinsulin and proinsulin/insulin ratios are secondary to increased demands on β-cell secretion induced by hyperglycemia and insulin resistance with no discernible influence of family history of diabetes.
http://jcem.endojournals.org/content/82/5/1629.full
INSULIN is produced post translational from its precursor molecule, proinsulin, by site-directed proteolysis in β-cell granules (1). Conversion involves cleavage at pairs of basic residues that link both the insulin A- and B-chains to C-peptide. Human proinsulin conversion has a preferred sequential route, such that cleavage at the B-chain/C-peptide junction occurs first, producing des-31,32 split proinsulin as the major conversion intermediate (2). Under normal circumstances, proinsulin conversion is largely completed before secretion and low plasma levels of intact proinsulin and conversion intermediates are found. Structural abnormalities in the proinsulin molecule can impair conversion, leading to the accumulation of proinsulin-like material in the circulation. Such defects show an autosomal dominant mode of inheritance and are the main cause of familial hyperproinsulinemia (3, 4, 5, 6, 7, 8). We report here the clinical and laboratory characteristics of a type 2 diabetic patient who had a novel mutation in the insulin gene, giving rise to impaired proinsulin conversion.
Red Cross in Syria
May 8, 2012
WHO Health Topics
May 7, 2012
Health topics
Financial crisis and global health
The global economic downturn is likely to have ripple effects on health and social spending, especially in developing countries. Protecting investments in health and social structures is essential to maintain stability and security, and accelerate economic recovery. The challenge facing the world now is to prevent an economic crisis becoming a social and health crisis.
Renin- angiotensin system suppression
April 12, 2012
Angiotensin receptor blockers and tumorigenesis
April 10, 2012
Curr Hypertens Rep. 2012 Apr 1. [Epub ahead of print]
Angiotensin Receptor Blockers and Tumorigenesis: Something To Be (or Not To Be) Concerned About?
Tchaikovski V, Lip GY.
Source
Haemostasis, Thrombosis and Vascular Biology Unit, University of Birmingham Centre for Cardiovascular Sciences, City Hospital Birmingham, Birmingham, B18 7QH, England, UK.
Abstract
The possibility of carcinogenic side effects of antihypertensive therapies due to their chronic administration has been raised multiple times in the past. Recently, the issue has again drawn attention, this time in relation to angiotensin receptor blockers (ARBs). This, among others, caused both American and European drug regulation authorities to review the underlying evidence concerning the relationship between this class of medications and potential adverse carcinogenic outcome. A plethora of both basic science and preclinical evidence has been generated, and three meta-analyses and one nationwide cohort have focused on this specific question. The current review aims to summarize the contemporary multidisciplinary evidence on whether ARBs may be associated with an increased risk of tumorigenesis.
PMID:
22467342
[PubMed - as supplied by publisher]
My Comment:
This possibility of tumorigenesis has come to my mind, because the structure of candesartan has -N-N- bonding.
http://en.wikipedia.org/wiki/File:Candesartan.svg
And vice verse
ACEI can suppress angiogenesis in hepatoma, not an effect to neglect
http://www.tumorres.com/tumor-stem-cell/31355.htm
http://www.dailymail.co.uk/health/article-1286404/Common-blood-pressure-drug-raises-cancer-risk.html
