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FOR THE U.K. PROSPECTIVE DIABETES STUDY GROUPOBJECTIVE -To evaluate the efficacy of the addition of insulin when maximal sulfonylurea therapy is inadequate in individuals with type 2 diabetes.RESEARCH DESIGN AND METHODS -Glycemic control, hypoglycemia, and body weight were monitored over 6 years in 826 patients with newly diagnosed type 2 diabetes in 8 of 23 U.K. Prospective Diabetes Study (UKPDS) centers that used a modified protocol. Patients were randomly allocated to a conventional glucose control policy, primarily with diet (n ϭ 242) or an intensive policy with insulin alone (n ϭ 245), as in the main study. However, for patients randomized to an intensive policy with sulfonylurea (n ϭ 339), insulin was added automatically if the fasting plasma glucose remained Ͼ108 mg/dl (6.0 mmol/l) despite maximal sulfonylurea doses.RESULTS -Over 6 years, ϳ53% of patients allocated to treatment with sulfonylurea required additional insulin therapy. Median HbA 1c in the sulfonylurea Ϯ insulin group was significantly lower (6.6%, interquartile range [IQR] 6.0 -7.6) than in the group taking insulin alone (7.1%, IQR 6.2-8.0; P ϭ 0.0066), and significantly more patients in the sulfonylurea Ϯ insulin group had an HbA 1c Ͻ7% (47 vs. 35%, respectively; P ϭ 0.011). Weight gain was similar in the intensive therapy groups, but major hypoglycemia occurred less frequently over all in the sulfonylurea (Ϯ insulin) group compared with the insulin alone group (1.6 vs. 3.2% per annum, respectively; P ϭ 0.017).CONCLUSIONS -Early addition of insulin when maximal sulfonylurea therapy is inadequate can significantly improve glycemic control without promoting increased hypoglycemia or weight gain. Diabetes Care 25:330 -336, 2002T he U.K. Prospective Diabetes Study (UKPDS) showed that intensive control of blood glucose with sulfonylurea or insulin, and with metformin in overweight patients, substantially reduced the risk of diabetic complications (1). The intensive glucose control policy used in the first 15 UKPDS centers (Glucose Study 1) required patients to remain on their allocated monotherapy, unless fasting plasma glucose (FPG) levels increased to Ͼ15 mmol/l or hyperglycemic symptoms ensued, to evaluate specific advantages or disadvantages of individual therapies. With the realization that progressive hyperglycemia was occurring in all randomized groups (2-4) and that additional therapy might be desirable at the stage of sulfonylurea inadequacy (5) rather than sulfonylurea failure, a modified protocol (Glucose Study 2) was introduced in the last eight UKPDS centers (6). This protocol, the aim of which was to determine whether a more aggressive glucose control policy could minimize hyperglycemic progression, differed only in that insulin therapy was added immediately in patients allocated to sulfonylurea therapy if maximal doses did not maintain FPG levels Ͻ108 mg/dl (6.0 mmol/l).A meta-analysis of randomized controlled trials (7) has shown that combining sulfonylurea and insulin therapy can improve metabolic control with significantly smal...

Protein delivery into cells is a potentially transformative tool for treating “undruggable” targets in diseases associated with protein deficiencies or mutations. The vast majority of these targets are accessed via the cytosol, a challenging prospect for proteins with therapeutic and diagnostic relevance. In this review we will present promising non-viral approaches for intracellular and ultimately cytosolic delivery of proteins using nanocarriers. We will also discuss the mechanistic properties that govern the efficacy of nanocarrier-mediated protein delivery, applications of nanomaterials, and key challenges and opportunities in the use of nanocarriers for intracellular protein delivery.

OBJECTIVE -Mortality from acute diabetes-related events is greatly raised in young adults with type 1 diabetes. Psychosocial and socioeconomic risk factors are examined for deaths from acute events separately from deaths due to other causes. RESEARCH DESIGN AND METHODS -This study had a nested case-control design.The cases were patients from the Diabetes UK cohort who died before age 40 years. Deaths were categorized as acute events or chronic conditions related to diabetes. Where possible, two matched control subjects were selected for each case. Data relating to psychosocial and socioeconomic factors and variables related to diabetes complications were extracted from the case notes. Risks of death were estimated by calculation of odds ratios (ORs).RESULTS -Case notes were obtained for 98 case and 137 control subjects. Fifty-one deaths were attributed to acute causes, 34 to chronic conditions related to diabetes, and the remaining 13 were unrelated to diabetes. Living alone (OR 4.4), past drug abuse (5.7), and previous psychiatric referral (4.6) were all significantly associated with death from acute events but not death from chronic conditions. There was no association between deaths from acute events and nephropathy, hypertension, neuropathy, or retinopathy, although all of these were associated with deaths from chronic conditions. CONCLUSIONS -The results indicate that psychosocial factors are powerful risk factors for mortality from acute events in patients with type 1 diabetes, although not for mortality from chronic conditions. The data enable the identification of a high-risk group suitable for targeting with preventive measures to reduce acute event mortality. Diabetes Care 28:1618 -1623, 2005M ortality in patients with type 1 diabetes is higher than in the general population at all ages (1). Previous results from the Diabetes UK (formerly British Diabetic Association) cohort study have indicated that at ages Ͻ40 years, mortality is increased approximately threefold in men and fivefold in women compared with mortality in the general population. After age 30, the majority of deaths can be attributed to longterm complications of diabetes, with cardiovascular disease the greatest single cause of death. In patients Ͻ30 years of age, mortality is predominantly due to either acute events related to diabetes or due to accidents and violence (2).If mortality is to be reduced in young patients with type 1 diabetes, then deaths from acute events need to be specifically addressed. It is likely that risk factors for mortality from acute events might be different from those related to deaths from long-term complications of type 1 diabetes. In particular, it is postulated that some psychosocial and socioeconomic variables might be more closely associated with deaths from acute events than with deaths from long-term complications. In the past 3 decades, there has been increasing interest in the relation of the psychosocial and socioeconomic status of young adults with diabetes to the management of their condition. It ...

To assess the full effect of diabetes on survival in elderly subjects, residents of Melton Mowbray aged 65, 70, 75, 80, and 85 years were screened by glucose tolerance test and followed up for 4.5 years. Death occurred in 56 of 520 normal subjects, 9 of 44 subjects with impaired glucose tolerance, 7 of 19 newly diagnosed diabetic subjects, and 27 of 52 known diabetic subjects. Diabetic subjects were 4.5 times (95% confidence interval 2.9-7.0) more likely to die than subjects with normal glucose tolerance. Thus elderly diabetic subjects have a substantially increased risk of death compared to their normal glucose tolerant peers.