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AimsTo evaluate the maintenance of efficacy and safety of insulin glargine 300 U/ml (Gla-300) versus glargine 100 U/ml (Gla-100) in people with type 2 diabetes mellitus (T2DM) using basal plus meal-time insulin for 12 months in the EDITION 1 trial. MethodsEDITION 1 was a multicentre, randomized, open-label, two-arm, phase IIIa study. Participants completing the initial 6-month treatment period continued to receive Gla-300 or Gla-100, as previously randomized, once daily for a further 6-month open-label extension phase. Changes in glycated haemoglobin (HbA1c) and fasting plasma glucose concentrations, insulin dose, hypoglycaemic events and body weight were assessed. ResultsOf 807 participants enrolled in the initial phase, 89% (359/404) assigned to Gla-300 and 88% (355/403) assigned to Gla-100 completed 12 months. Glycaemic control was sustained in both groups (mean HbA1c: Gla-300, 7.24%; Gla-100, 7.42%), with more sustained HbA1c reduction for Gla-300 at 12 months: least squares mean difference Gla-300 vs Gla-100: HbA1c -0.17 [95% confidence interval (CI) -0.30 to -0.05]%. The mean daily basal insulin dose at 12 months was 1.03 U/kg for Gla-300 and 0.90 U/kg for Gla-100. Lower percentages of participants had 1 confirmed [3.9 mmol/l (70 mg/dl)] or severe hypoglycaemic event with Gla-300 than Gla-100 at any time of day [24 h; 86 vs 92%; relative risk 0.94 (95% CI 0.89-0.99)] and during the night [54 vs 65%; relative risk 0.84 (95% CI 0.75-0.94)], while the annualized rates of such hypoglycaemic events were similar. No between-treatment differences in adverse events were apparent. ConclusionDuring 12 months of treatment of T2DM requiring basal and meal-time insulin, glycaemic control was better sustained and fewer individuals reported hypoglycaemia with Gla-300 than with Gla-100. The mean basal insulin dose was higher with Gla-300 compared with Gla-100, but total numbers of hypoglycaemic events and overall tolerability did not differ between treatments.

Aims To ascertain whether pre-meal administration of 50% insulin lispro and 50% neutral protamine lispro (NPL), given as a fixed mixture (Humalog® Mix50™, Eli Lilly) (Mix50), provides satisfactory glycaemic control throughout the day compared with pre-meal human soluble (regular) insulin as a basal-bolus regimen in people with Type 1 diabetes. Both regimens included bedtime human isophane (NPH) insulin. Methods This was a multinational, multicentre, randomized, open-label, two-period crossover comparison of two insulin treatments for two 12-week periods in 109 patients with Type 1 diabetes. The protocol provided preliminary evaluations of dose requirements and recommendations for insulin dose adjustment when switching regimens on the basis of blood glucose (BG) values. Eight-point BG profiles, frequency of hypoglycaemia, HbA1c, insulin dose, time of injection, and frequency of snacking were assessed during each treatment. Results Total daily insulin dose was similar for both treatments, but the total pre-meal doses were higher (P

Maintenance of long-term near-normoglycemia by intensive therapy largely, if not fully, prevents the onset of microangiopathic complications and delays progression of complications in type 1 diabetic patients. However, intensive therapy has been reported to increase the frequency of severe hypoglycemia. In addition, a number of experimental studies have shown that a few episodes of mild, recurrent hypoglycemia blunt the symptom and hormonal responses to hypoglycemia over the next few days. At present, the critical "post-DCCT" (Diabetes Control and Complications Trial) questions are: is it possible to maintain long-term HbA1c7.0%, first, without increasing the frequency of severe hypoglycemia, and second, without increasing the frequency of mild, recurrent hypoglycemia? The answer is yes. The key factors are use of a physiological model of insulin replacement and the education of patients to appropriate the decision of insulin dose based on blood glucose monitoring and eating patterns. Hypoglycemia unawareness should be suspected whenever HbA1c is6.0 (upper normal limit 5.5%) and the patient does not report autonomic symptoms when their blood glucose level is3.0 mmol/l. The unaware patients should be treated with a short-term program of meticulous prevention of hypoglycemia, which reverses the abnormalities of responses of symptoms, hormonal counterregulation, and brain cognitive function. In turn, reversal of these abnormalities decreases the risk for severe hypoglycemia. Importantly, a program of meticulous prevention of hypoglycemia does not result in loss of long-term near-normoglycemia, i.e., it is compatible with the glycemic targets of intensive therapy.

To establish whether lispro may be a suitable short-acting insulin preparation for meals in intensive treatment of Type 1 diabetes mellitus (DM) in patients already in chronic good glycaemic control with conventional insulins, 69 patients on intensive therapy (4 daily s.c. insulin injections, soluble at each meal, NPH at bedtime, HbA1c7.5%) were studied with an open, cross-over design for two periods of 3 months each (lispro or soluble). The % HbA1c and frequency of hypoglycaemia were assessed under four different conditions (Groups I-IV). Lispro was always injected at mealtime, soluble 10-40 min prior to meals (with the exception of Group IV). Bedtime NPH was continued with both treatments. When lispro replaced soluble with no increase in number of daily NPH injections (Group I, n = 15), HbA1c was no different (p = NS), but frequency of hypoglycaemia was greater (p0.05). When NPH was given 3-4 times daily, lispro (Group II, n = 18), but not soluble (Group III, n = 12) decreased HbA1c by 0.35 +/- 0.25% with no increase in hypoglycaemia. When soluble was injected at mealtimes, HbA1c increased by 0.18 +/- 0.15% and hypoglycaemia was more frequent than when soluble was injected 10-40 min prior to meals (Group IV, n = 24) (p0.05). It is concluded that in intensive management of Type 1 DM, lispro is superior to soluble in terms of reduction of % HbA1c and frequency of hypoglycaemia, especially for those patients who do not use a time interval between insulin injection and meal. However, these goals cannot be achieved without optimization of basal insulin.

Hypoglycaemia unawareness, a frequent syndrome in insulin-dependent diabetes mellitus (IDDM), involves a decrease or absence of perception of specific symptoms which normally inform the subject that plasma glucose is decreasing to dangerous levels leading to neuroglycopenia. Without warning symptoms, IDDM patients are unable to take measures (e.g. eating) to prevent severe neuroglycopenia (unconsciousness). As hypoglycaemia unawareness is associated with impaired glucose counterregulation, especially reduced adrenaline responses, it can lead to severe hypoglycaemia. Various studies in animals and humans have indicated that hypoglycaemia unawareness is largely, if not entirely, secondary to increased brain glucose transport due to recurrent or chronic hypoglycaemia. In fact, meticulous prevention of hypoglycaemia largely restores the warning symptoms and adrenaline responses, at least in short-term IDDM. In long-term IDDM, recovery is less complete. Diabetologists and IDDM patients need to be familiar with hypoglycaemia unawareness and how to prevent or treat it. Intensive therapy strictly for normoglycaemia may actually increase the frequency of hypoglycaemia and hypoglycaemia unawareness. However, if intensive therapy is combined with a hypoglycaemia prevention programme, the percentage of HbA1c can be maintained below risk values for the onset or progression of complications, and the frequency of hypoglycaemia can be kept low. Under these conditions, IDDM patients can maintain the warning symptoms and adrenaline response to hypoglycaemia, ensuring a vital backup system for safe intensive therapy of IDDM.

To assess the short-term metabolic effects a long-acting non-sulphydryl ACE-inhibitor benazepril on glycaemic control in Type 2 diabetes mellitus and arterial hypertension, 10 hypertensive diabetic patients treated with glibenclamide were studied in a double-blind, crossover fashion over two 10-day periods in which either benazepril (10 mg/day) or placebo was given. At the end of the 10 day treatment, both blood pressure and plasma glucose concentrations were lower after benazepril versus placebo (benazepril, blood pressure: 143 +/- 11/83 +/- 5 mmHg, plasma glucose: 7.1 +/- 1.2 mmol/l; placebo: blood pressure: 157 +/- 10/99 +/- 2 mmHg, plasma glucose: 8.2 +/- 1 mmol/l, p0.05). In response to an oral glucose tolerance test combined with 1 mg intravenous glibenclamide, plasma glucose levels were lower after benazepril versus placebo (0-460 min: 8.4 +/- 0.8 versus 10.5 +/- 0.9 mmol/l, p0.05), whereas plasma insulin, C-peptide and glibenclamide concentrations were not different. It is concluded that a short-term administration of benazepril in Type 2 diabetes mellitus reduces blood pressure and improves blood glucose control, most likely by decreasing insulin resistance.

The glucose counterregulatory system is one of the most important homeostatic systems in physiology, since it normally prevents hypoglycaemia or, should it occur for any reason such as insulin administration, limits the severity of hypoglycaemia and ultimately may restore normoglycaemia. In normal nondiabetic subjects, activation of counterregulation does not result in overt hyperglycaemia in the post-absorptive state, because the pancreatic beta-cell increases insulin secretion. On the contrary, in subjects with insulin-dependent diabetes mellitus (IDDM) whose pancreatic B-cell cannot respond to an increase in plasma glucose, activated counterregulation may easily result in overt hyperglycaemia. There are two different circumstances under which counterregulation may contribute to excessive hyperglycaemia in IDDM, namely nonhypoglycaemic nocturnal activation of counterregulation (dawn phenomenon), and hypoglycaemic activation of counterregulation (Somogyi phenomenon). The dawn phenomenon is an increase in insulin requirements which occurs between 04.00 and 08.00 h in the absence of preceding hypoglycaemia and concomitant hypoinsulinemia. It is caused by a decrease in hepatic and extrahepatic sensitivity to insulin induced by the nocturnal secretion of growth hormone. The dawn phenomenon may contribute importantly to fasting hyperglycaemia in IDDM, because usually plasma insulin concentration following the pre-supper insulin injection decreases after 04.00 h, i.e. a time at which plasma insulin concentration should instead increase to maintain normoglycaemia. The Somogyi phenomenon is best defined as hyperglycaemia following hypoglycaemia and is caused by the insulin resistance induced by hypoglycaemic-activation of counterregulation. Although insulin resistance following hypoglycaemia is a constant event in IDDM, post-hypoglycaemic hyperglycaemia is not the rule. For example, if the responses of counterregulatory hormones to nocturnal hypoglycaemia are blunted, or plasma insulin concentration following hypoglycaemia is inappropriately high, post-hypoglycaemic insulin resistance is not powerful enough to result in overt hyperglycaemia in the fasting state. However, post-breakfast plasma glucose may be exaggerately elevated following nocturnal hypoglycaemia even in the case that fasting plasma glucose is only modestly increased. It is important to prevent nocturnal hypoglycaemia, not only to protect brain function, but also to prevent insulin resistance which may easily result in exaggerated hyperglycaemia and initiate the vicious circle "hypoglycaemia-hyperglycaemia-increase in insulin dose-risk for subsequent hypoglycaemia", and so on.

To compare glucose counterregulatory mechanisms during short-term hypoglycemia and prolonged hypoglycemia, insulin was infused either intravenously (160 mU X M-2 X min) for 10 min or subcutaneously (15 mU X M-2 X min) for 12 h in normal volunteers. With each type of insulin infusion, hypoglycemia (approximately 50 mg/dl) was either allowed to develop or was prevented (control experiments) by the glucose-clamp technique. During prolonged hypoglycemia, both increased glucose production (1.55 +/- 0.05 versus 0.33 +/- 0.14 mg X kg-1 X min in control experiments at 12 h, P less than 0.01) and suppressed glucose utilization (1.55 +/- 0.06 versus 3.17 +/- 0.15 mg X kg-1 X min in control studies at 12 h, P less than 0.01) were involved in counterregulation. During short-term hypoglycemia, only increased glucose production (3.23 +/- 0.33 versus 0.06 +/- 0.03 mg X kg-1 X min in control experiments at 60 min) was involved, since glucose clearance actually increased (3.99 +/- 0.20 versus 2.88 +/- 0.02 ml X kg-1 X min in control experiments at 60 min, P less than 0.01). Estimated portal venous insulin concentrations decreased 40% (basal 24 +/- 3 versus 14 +/- 1 mU/ml at 60 min, P less than 0.01) in the short-term hypoglycemia experiments but remained at basal levels (basal 25 +/- 1 versus approximately 26 microU/min between 1 and 12 h) during prolonged hypoglycemia. Despite the fact that hypoglycemia was more gradually induced in the prolonged hypoglycemia model, peak counterregulatory hormone responses were at least as great as those during short-term hypoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: The potential of an increased risk of breast cancer in women with diabetes has been the subject of a great deal of recent research. Methods: A meta-analysis was undertaken using a random effects model to investigate the association between diabetes and breast cancer risk. Results: Thirty-nine independent risk estimates were available from observational epidemiological studies. The summary relative risk (SRR) for breast cancer in women with diabetes was 1.27 (95% confidence interval (CI), 1.16–1.39) with no evidence of publication bias. Prospective studies showed a lower risk (SRR 1.23 (95% CI, 1.12–1.35)) than retrospective studies (SRR 1.36 (95% CI, 1.13–1.63)). Type 1 diabetes, or diabetes in pre-menopausal women, were not associated with risk of breast cancer (SRR 1.00 (95% CI, 0.74–1.35) and SRR 0.86 (95% CI, 0.66–1.12), respectively). Studies adjusting for body mass index (BMI) showed lower estimates (SRR 1.16 (95% CI, 1.08–1.24)) as compared with those studies that were not adjusted for BMI (SRR 1.33 (95% CI, 1.18–1.51)). Conclusion: The risk of breast cancer in women with type 2 diabetes is increased by 27%, a figure that decreased to 16% after adjustment for BMI. No increased risk was seen for women at pre-menopausal ages or with type 1 diabetes.