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Sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy. This pharmacogenetic response to sulfonylureas may result from the closing of mutant K(ATP) channels, thereby increasing insulin secretion in response to incretins and glucose metabolism. (ClinicalTrials.gov number, NCT00334711 [ClinicalTrials.gov].).

There is increased recognition that determinants of health should be investigated in a life-course perspective. Retirement is a major transition in the life course and offers opportunities for changes in physical activity that may improve health in the aging population. The authors examined the effect of retirement on changes in physical activity in the GLOBE Study, a prospective cohort study known by the Dutch acronym for "Health and Living Conditions of the Population of Eindhoven and surroundings," 1991-2004. They followed respondents (n = 971) by postal questionnaire who were employed and aged 40-65 years in 1991 for 13 years, after which they were still employed (n = 287) or had retired (n = 684). Physical activity included 1) work-related transportation, 2) sports participation, and 3) nonsports leisure-time physical activity. Multinomial logistic regression analyses indicated that retirement was associated with a significantly higher odds for a decline in physical activity from work-related transportation (odds ratio (OR) = 3.03, 95% confidence interval (CI): 1.97, 4.65), adjusted for sex, age, marital status, chronic diseases, and education, compared with remaining employed. Retirement was not associated with an increase in sports participation (OR = 1.12, 95% CI: 0.71, 1.75) or nonsports leisure-time physical activity (OR = 0.80, 95% CI: 0.54, 1.19). In conclusion, retirement introduces a reduction in physical activity from work-related transportation that is not compensated for by an increase in sports participation or an increase in nonsports leisure-time physical activity.

HNF-1beta mutations are a rare cause of neonatal diabetes as well as pancreatic exocrine and endocrine dysfunction. Low birth weight is a common feature of patients with HNF-1beta mutations and is consistent with reduced insulin secretion in utero. These findings support a key role for HNF-1beta in early pancreatic progenitor cells in man.

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Aims/hypothesis Activating mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the K ATP channels in pancreatic beta cells are a common cause of neonatal diabetes. One-third of patients also have developmental delay, which probably results from mutated K ATP channels in muscle, nerve and brain. Sulfonylureas, which bind to the sulfonylurea receptor 1 subunit of the K ATP channel, can replace insulin injections in patients with KCNJ11 mutations. The aim of this study was to investigate the long-term outcome and impact on neurological features of sulfonylurea treatment.

This is the first clear report of cognitive function improving in a patient with the neurological features associated with a K(ATP) channel mutation following transfer to sulphonylureas. The finding of cognitive improvement suggests that glibenclamide is likely to be acting directly on the brain and not just on nerve and muscle, improving muscle strength.

Permanent neonatal diabetes (PNDM) is diagnosed in the first three months of life and is a major management problem as patients require lifelong insulin injections. Recently, activating mutations in the KCNJ11 gene which encodes the Kir6.2 subunit of the KATP channels in the pancreatic beta-cells were found to be an important cause of PNDM. The mutated KATP channels do not close in the presence of adenosine triphosphate (ATP) so the beta-cell membrane is hyperpolarized and insulin secretion does not occur. Some patients have DEND syndrome (developmental delay, epilepsy and neonatal diabetes) with the neurological features arising from mutated KATP channels in muscle, nerve and brain. Defining a genetic aetiology has not only given insights into clinical classification and disease mechanism, but has also influenced treatment. Sulphonylureas, by binding the sulphonylurea receptor, can close the KATP channel. This has led to patients who were insulin-dependent being able to discontinue insulin injections and achieve excellent control with sulphonylurea tablets. In this article we discuss the work that established Kir6.2 mutations as a common cause of neonatal diabetes, the clinical features, the underlying mechanism and the impact on patient treatment.