Stratified patient-centered care in type 2 diabetes: a cluster-randomized, controlled clinical trial of effectiveness and cost-effectiveness.

OBJECTIVE: Diabetes treatment should be effective and cost-effective. HbA1c-associated complications are costly. Would patient-centered care be more (cost-) effective if it was targeted to patients within specific HbA1c ranges? RESEARCH DESIGN AND METHODS: This prospective, cluster-randomized, controlled trial involved 13 hospitals (clusters) in the Netherlands and 506 patients with type 2 diabetes randomized to patient-centered (n=237) or usual care (controls) (n=269). Primary outcomes were change in HbA1c and quality-adjusted life years (QALYs); costs and incremental costs (USD) after 1 year were secondary outcomes. We applied nonparametric bootstrapping and probabilistic modeling over a lifetime using a validated Dutch model. The baseline HbA1c strata were <7.0% (53 mmol/mol), 7.0-8.5%, and >8.5% (69 mmol/mol). RESULTS: Patient-centered care was most effective and cost-effective in those with baseline HbA1c>8.5% (69 mmol/mol). After 1 year, the HbA1c reduction was 0.83% (95% CI 0.81-0.84%) (6.7 mmol/mol [6.5-6.8]), and the incremental cost-effectiveness ratio (ICER) was 261 USD (235-288) per QALY. Over a lifetime, 0.54 QALYs (0.30-0.78) were gained at a cost of 3,482 USD (2,706-4,258); ICER 6,443 USD/QALY (3,199-9,686). For baseline HbA1c 7.0-8.5% (53-69 mmol/mol), 0.24 QALY (0.07-0.41) was gained at a cost of 4,731 USD (4,259-5,205); ICER 20,086 USD (5,979-34,193). Care was not cost-effective for patients at a baseline HbA1c<7.0% (53 mmol/mol). CONCLUSIONS: Patient-centered care is more valuable when targeted to patients with HbA1c>8.5% (69 mmol/mol), confirming clinical intuition. The findings support treatment in those with baseline HbA1c 7-8.5% (53-69 mmol/mol) and demonstrate little to no benefit among those with HbA1c<7% (53 mmol/mol). Further studies should assess different HbA1c strata and additional risk profiles to account for heterogeneity among patients.

Mutations in the glucokinase gene of the fetus result in reduced placental weight.

OBJECTIVE: In human pregnancy, placental weight is strongly associated with birth weight. It is uncertain whether there is regulation of the placenta by the fetus or vice versa. We aimed to test the hypothesis that placental growth is mediated, either directly or indirectly, by fetal insulin. RESEARCH DESIGN AND METHODS: Birth weight and placental weight were measured in 43 offspring of 21 parents with mutations in the glucokinase (GCK) gene (25 had inherited the mutation and 18 had not), which results in reduced fetal insulin secretion. Birth weight, placental weight, umbilical cord insulin, and maternal glucose and insulin concentrations were measured in 573 nondiabetic, healthy, term pregnancies. RESULTS: GCK mutation carriers were lighter and also had smaller placentas (610 vs. 720 g, P = 0.042). This difference was also seen in 17 discordant sibling pairs (600 vs. 720 g, P = 0.003). GCK mRNA was not detected in the placenta by RT-PCR. In the normal pregnancies, placental weight was strongly correlated with birth weight (r = 0.61, P < 0.001). Cord insulin concentrations were directly related to placental weight (r = 0.28) and birth weight (r = 0.36) (P < 0.001 for both). CONCLUSIONS: These results suggest that insulin, directly or indirectly, plays a role in placental growth, especially as a mutation in the GCK gene, which is known to only alter fetal insulin secretion, results in altered placental weight. This finding is consistent with the preferential localization of the insulin receptors in the fetal endothelium of the placenta in the last trimester of pregnancy.

Aging, retirement, and changes in physical activity: prospective cohort findings from the GLOBE study.

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.

Monogenic diabetes in children and young adults: Challenges for researcher, clinician and patient.

Monogenic diabetes results from one or more mutations in a single gene which might hence be rare but has great impact leading to diabetes at a very young age. It has resulted in great challenges for researchers elucidating the aetiology of diabetes and related features in other organ systems, for clinicians specifying a diagnosis that leads to improved genetic counselling, predicting of clinical course and changes in treatment, and for patients to altered treatment that has lead to coming off insulin and injections with no alternative (Glucokinase mutations), insulin injections being replaced by tablets (e.g. low dose in HNFalpha or high dose in potassium channel defects -Kir6.2 and SUR1) or with tablets in addition to insulin (e.g. metformin in insulin resistant syndromes). Genetic testing requires guidance to test for what gene especially given limited resources. Monogenic diabetes should be considered in any diabetic patient who has features inconsistent with their current diagnosis (unspecified neonatal diabetes, type 1 or type 2 diabetes) and clinical features of a specific subtype of monogenic diabetes (neonatal diabetes, familial diabetes, mild hyperglycaemia, syndromes). Guidance is given by clinical and physiological features in patient and family and the likelihood of the proposed mutation altering clinical care. In this article, I aimed to provide insight in the genes and mutations involved in insulin synthesis, secretion, and resistance, and to provide guidance for genetic testing by showing the clinical and physiological features and tests for each specified diagnosis as well as the opportunities for treatment.

Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.

BACKGROUND: Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, cause 30 to 58 percent of cases of diabetes diagnosed in patients under six months of age. Patients present with ketoacidosis or severe hyperglycemia and are treated with insulin. Diabetes results from impaired insulin secretion caused by a failure of the beta-cell K(ATP) channel to close in response to increased intracellular ATP. Sulfonylureas close the K(ATP) channel by an ATP-independent route. METHODS: We assessed glycemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant K(ATP) channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes. RESULTS: A total of 44 patients (90 percent) successfully discontinued insulin after receiving sulfonylureas. The extent of the tolbutamide blockade of K(ATP) channels in vitro reflected the response seen in patients. Glycated hemoglobin levels improved in all patients who switched to sulfonylurea therapy (from 8.1 percent before treatment to 6.4 percent after 12 weeks of treatment, P<0.001). Improved glycemic control was sustained at one year. Sulfonylurea treatment increased insulin secretion, which was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose. Exogenous glucagon increased insulin secretion only in the presence of sulfonylureas. CONCLUSIONS: 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].).

Activating mutations in the gene encoding Kir6.2 alter fetal and postnatal growth and also cause neonatal diabetes.

CONTEXT: Birth weight is a bioassay for fetal insulin secretion because altered insulin secretion in utero alters insulin-mediated growth. Activating mutations in Kir6.2 are the major cause of neonatal diabetes and reduce insulin secretion by altering the closure of the beta-cell ATP-sensitive potassium channel in the presence of ATP. OBJECTIVE: Our objective was to examine fetal and postnatal growth in patients with activating Kir6.2 mutations and identify whether this was modified by severity of mutation or maternal diabetes. PATIENTS AND METHODS: We used sd scores (SDS) for birth and postnatal growth in an international series of patients (n = 49) with Kir6.2 mutations and related this to their clinical phenotype. RESULTS: Birth weight was greatly reduced [-1.73 (-3.68 to 1.41), median (range) SDS], but there was postnatal catch-up because present weight was normal [-0.37 (-4.37 to 2.34) SDS]. Catch-up growth for height and weight was not seen until insulin treatment was started. Birth weight was not influenced by severity of postnatal phenotype but was increased by maternal diabetes -0.12 vs. -1.81 SDS (P = 0.037). Patients with the severe neurological developmental delay, epilepsy, and neonatal diabetes syndrome did not catch up (present weight -2.2 vs. -0.24 SDS (P = 0.003). CONCLUSIONS: Kir6.2 mutations greatly reduce fetal insulin secretion and hence fetal growth, but this is independent of mutation severity. Increased fetal growth in response to maternal diabetes suggests that either the Kir6.2 mutated fetal beta-cell is still glucose responsive or there is a non-insulin-mediated increase in fetal growth. Postnatal catch-up requires insulin treatment but is complete, except in those with epilepsy.

Mutations in the Kir6.2 subunit of the KATP channel and permanent neonatal diabetes: new insights and new treatment.

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.

Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

BACKGROUND: Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. METHODS: We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. RESULTS: Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. CONCLUSIONS: Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas.