Efficacy and safety of lixisenatide in elderly (≥65 years old) and very elderly (≥75 years old) patients with type 2 diabetes: an analysis from the GetGoal phase III programme.

BACKGROUND: The objective of this article is to evaluate the pharmacokinetics, efficacy and safety of lixisenatide (subcutaneous injection) in elderly (≥65 years old) and very elderly (≥75 years old) patients with type 2 diabetes mellitus. METHODS: We conducted a phase I, single-centre, open-label study to evaluate the safety and pharmacokinetics of a single lixisenatide 20 µg dose and a pooled analysis of six randomized, placebo-controlled, phase III studies (12-month or 24-month duration) that evaluated glycaemic parameters and safety in patients receiving lixisenatide 20 µg once daily or placebo. RESULTS: The pharmacokinetics study included 36 healthy subjects, including 18 elderly healthy subjects (≥65 years old) and 18 matched young healthy subjects (18-45 years old). The pooled analysis included 3188 patients, including 2565 patients <65 years old and 623 patients ≥65 years old (including 79 patients ≥75 years old). Mean exposure with lixisenatide 20 µg was ~30% higher in elderly than in young subjects, and the terminal half-life was prolonged by ~1.6 times. Maximum concentration (C(max)) and time to C(max) (t(max)) were comparable in both groups. Equal numbers of elderly and young subjects reported treatment-emergent adverse events, the majority of which were gastrointestinal disorders. In the pooled analysis, lixisenatide 20 µg once daily provided significant reductions in HbA1c versus placebo for all age groups. There was a similar incidence of treatment-emergent adverse events across all age groups (range: 69-73%). The incidence of symptomatic hypoglycaemia was generally comparable between lixisenatide-treated and placebo-treated patients. CONCLUSION: These data suggest that lixisenatide is effective and well tolerated in elderly and very elderly patients with type 2 diabetes mellitus.

The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications.

The hyperglycemic activity of pancreatic extracts was encountered some 80 yr ago during efforts to optimize methods for the purification of insulin. The hyperglycemic substance was named "glucagon," and it was subsequently determined that glucagon is a 29-amino acid peptide synthesized and released from pancreatic alpha-cells. This article begins with a brief overview of the discovery of glucagon and the contributions that somatostatin and a sensitive and selective assay for pancreatic (vs. gut) glucagon made to understanding the physiological and pathophysiological roles of glucagon. Studies utilizing these tools to establish the function of glucagon in normal nutrient homeostasis and to document a relative glucagon excess in type 2 diabetes mellitus (T2DM) and precursors thereof are then discussed. The evidence that glucagon excess contributes to the development and maintenance of fasting hyperglycemia and that failure to suppress glucagon secretion contributes to postprandial hyperglycemia is then reviewed. Although key human studies are emphasized, salient animal studies highlighting the importance of glucagon in normal and defective glucoregulation are also described. The past eight decades of research in this area have led to development of new therapeutic approaches to treating T2DM that have been shown to, or are expected to, improve glycemic control in patients with T2DM in part by improving alpha-cell function or by blocking glucagon action. Accordingly, this review ends with a discussion of the status and therapeutic potential of glucagon receptor antagonists, alpha-cell selective somatostatin agonists, glucagon-like peptide-1 agonists, and dipeptidyl peptidase-IV inhibitors. Our overall conclusions are that there is considerable evidence that relative hyperglucagonemia contributes to fasting and postprandial hyperglycemia in patients with T2DM, and there are several new and emerging pharmacotherapies that may improve glycemic control in part by ameliorating the hyperglycemic effects of this relative glucagon excess.

Diabetes mellitus and gastric emptying: questions and issues in clinical practice.

It is long known that both type 1 and type 2 diabetes can be associated with changes in gastric emptying; a number of publications have linked diabetes to delayed gastric emptying of variable severity and often with poor relationship to gastrointestinal symptomatology. In contrast, more recent studies have reported accelerated gastric emptying when adjusted for glucose concentration in patients with diabetes, indicating a reciprocal relationship between gastric emptying and ambient glucose concentrations. This review proposes that gastroparesis or gastroparesis diabeticorum, a severe condition characterized by a significant impairment of gastric emptying accompanied by severe nausea, vomiting, and malnutrition, is often overdiagnosed and not well contrasted with delays in gastric emptying. The article offers a clinically relevant definition of gastroparesis that should help differentiate this rare condition from (often asymptomatic) delays in gastric emptying. The fact that delayed gastric emptying can also be observed in non-diabetic individuals under experimental conditions in which hyperglycaemia is artificially induced suggests that a delay in gastric emptying rate when blood glucose concentrations are high is actually an appropriate physiological response to hyperglycaemia, slowing further increases in blood glucose. The article discusses the strengths and weaknesses of various methodologies for assessing gastric emptying, especially with respect to the diabetes population, and reviews newer diabetes therapies that decelerate the rate of gastric emptying. These therapies may be a beneficial tool in managing postprandial hyperglycaemia because they attenuate rapid surges in glucose concentrations by slowing the delivery of meal-derived glucose.

Is a history of gestational diabetes related to risk factors for coronary heart disease?

Coronary heart disease (CHD) risk in 20 non-diabetic women with and 20 without a distant history of gestational diabetes (hGDM), matched on age, body mass index, and time since GDM-affected pregnancy, was compared in a case control study. Women with an hGDM had lower high-density lipoprotein cholesterol (HDL-c), p = .02, and higher triglycerides, p < or = .001, versus controls. The combination of high triglycerides and low HDL-c occurred in 25% of hGDM cases versus 0% of controls, p

Guideline for management of postmeal glucose.

An estimated 246 million people worldwide have diabetes. Diabetes is a leading cause of death in most developed countries, and is reaching epidemic proportions in many developing and newly industrialized nations. Poorly controlled diabetes is associated with the development of renal failure, vision loss, macrovascular diseases and amputations. Large controlled clinical trials have demonstrated that intensive treatment of diabetes can significantly decrease the development and/or progression of microvascular complications of diabetes. There appears to be no glycaemic threshold for reduction of diabetes complications; the lower the glycated haemoglobin (HbA1c), the lower the risk. The progressive relationship between plasma glucose levels and cardiovascular risk extends well below the diabetic threshold. Until recently, the predominant focus of therapy has been on lowering HbA1c levels, with a strong emphasis on fasting plasma glucose. Although control of fasting hyperglycaemia is necessary, it is usually insufficient to obtain optimal glycaemic control. A growing body of evidence suggests that reducing postmeal plasma glucose excursions is as important, or perhaps more important for achieving HbA1c goals. This guideline reviews the evidence on the harmful effects of elevated postmeal glucose and makes recommendations on its treatment, assessment and targets.

Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes Importance of postprandial glycemia to achieve target HbA1c levels.

OBJECTIVE: HbA1c values reflect overall glycemic exposure over the past 2-3 months and are determined by both fasting (FPG) and postprandial plasma glucose (PPG) levels. Cross-sectional studies suggest that attainment of HbA1c goals requires specific targeting of postprandial hyperglycemia. RESEARCH DESIGN AND METHODS: We undertook a prospective intervention trial to assess the relative contribution of controlling FPG and PPG for achieving recommended HbA1c goals. One hundred and sixty-four patients (90 male and 74 female) with unsatisfactory glycemic control (HbA1c >/=7.5%) were enrolled in an individualized forced titration intensified treatment program. RESULTS: After 3 months HbA1c levels decreased from 8.7+/-0.1 to 6.5+/-0.1% (p<0.001); FPG decreased from 174+/-4 to 117+/-2mg/dl (p<0.001); PPG decreased from 224+/-4 to 159+/-3mg/dl (p<0.001) and daylong hyperglycemia (average of premeal, postprandial and bedtime plasma glucose excluding FPG) decreased from 199+/-4 to 141+/-2mg/dl (p<0.0001). Patients' weight remained unchanged (84.0+/-1.4kg versus 82.9+/-1.5kg, p=0.36). No severe hypoglycemia occurred. Only 64% of patients achieving FPG targets of <100mg/dl achieved an HbA1c target of <7% whereas 94% of patients achieving the postprandial target of <140mg/dl did. Decreases in PPG accounted for nearly twice as much for the decreases in HbA1c as did decreases in FPG. PPG accounted approximately 80% of HbA1c when HbA1c was <6.2% and only about 40% when HbA1c was above 9.0%. CONCLUSIONS: Control of fasting hyperglycemia is necessary but usually insufficient for achieving HbA1c goals <7%. Control of postprandial hyperglycemia is essential for achieving recommended HbA1c goals.

Type 2 diabetes mellitus is associated with multiple cardiometabolic risk factors.

The risk for cardiovascular disease (CVD) is multifactorial and includes such risk factors as diabetes, hypertension, smoking, and dyslipidemia. Thus, targeting the hyperglycemia in type 2 diabetes mellitus (DM) alone will not eliminate all of the excess cardiovascular risk; rather aggressive treatment is needed for all of the modifiable cardiometabolic risk factors. Therapeutic lifestyle change is considered primary therapy for hyperglycemia in type 2 DM. Currently, however, the focus in treatment is on preventing CVD rather than controlling glucose, lipid, or blood pressure (BP) levels. The American Diabetes Association guidelines identify low-density lipoprotein cholesterol as the first priority of lipid lowering, with optimal level set at <100 mg/dL (2.6 mmol/L). To reach the target BP level of <130/85 mm Hg, >65% of patients with DM and hypertension will require 2 or more different antihypertensive drugs. Strategies that combine thiazolidinediones and statins may have complementary effects on cardiovascular risk-factor profiles in type 2 DM, in addition to controlling glycemia. Despite the range of treatment options available, therapeutic agents that target new steps in the progression of CVD are needed, as patients with type 2 DM remain at increased risk and many do not achieve therapeutic targets with the drugs available.

Different mechanisms for impaired fasting glucose and impaired postprandial glucose tolerance in humans.

OBJECTIVE: To compare the pathophysiology of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in a more comprehensive and standardized fashion than has hitherto been done. RESEARCH DESIGN AND METHODS: We studied 21 individuals with isolated IFG (IFG/normal glucose tolerance [NGT]), 61 individuals with isolated IGT (normal fasting glucose [NFG]/IGT), and 240 healthy control subjects (NFG/NGT) by hyperglycemic clamps to determine first- and second-phase insulin release and insulin sensitivity. Homeostasis model assessment (HOMA) indexes of beta-cell function (HOMA-%B) and insulin resistance (HOMA-IR) were calculated from fasting plasma insulin and glucose concentrations. RESULTS: Compared with NFG/NGT, IFG/NGT had similar fasting insulin concentrations despite hyperglycemia; therefore, HOMA-IR was increased approximately 30% (P < 0.05), but clamp-determined insulin sensitivity was normal (P > 0.8). HOMA-%B and first-phase insulin responses were reduced approximately 35% (P < 0.002) and approximately 30% (P < 0.02), respectively, but second-phase insulin responses were normal (P > 0.5). NFG/IGT had normal HOMA-IR but approximately 15% decreased clamp-determined insulin sensitivity (P < 0.03). Furthermore, HOMA-%B was normal but both first-phase (P < 0.0003) and second-phase (P < 0.0001) insulin responses were reduced approximately 30%. IFG/NGT differed from NFG/IGT by having approximately 40% lower HOMA-%B (P < 0.012) and approximately 50% greater second-phase insulin responses (P < 0.005). CONCLUSIONS: Since first-phase insulin responses were similarly reduced in IFG/NGT and NFG/IGT, we conclude that IFG is due to impaired basal insulin secretion and preferential resistance of glucose production to suppression by insulin, as reflected by fasting hyperglycemia despite normal plasma insulin concentrations and increased HOMA-IR, whereas IGT mainly results from reduced second-phase insulin release and peripheral insulin resistance, as reflected by reduced clamp-determined insulin sensitivity.

Renal glucose metabolism in normal physiological conditions and in diabetes.

The kidney plays an important role in glucose homeostasis via gluconeogenesis, glucose utilization, and glucose reabsorption from the renal glomerular filtrate. After an overnight fast, 20-25% of glucose released into the circulation originates from the kidneys through gluconeogenesis. In this post-absorptive state, the kidneys utilize about 10% of all glucose utilized by the body. After glucose ingestion, renal gluconeogenesis increases and accounts for approximately 60% of endogenous glucose release in the postprandial period. Each day, the kidneys filter approximately 180g of glucose and virtually all of this is reabsorbed into the circulation. Hormones (most importantly insulin and catecholamines), substrates, enzymes, and glucose transporters are some of the various factors influencing the kidney's role. Patients with type 2 diabetes have an increased renal glucose uptake and release in the fasting and the post-prandial states. Additionally, glucosuria in these patients does not occur at plasma glucose levels that would normally produce glucosuria in healthy individuals. The major abnormality of renal glucose metabolism in type 1 diabetes appears to be impaired renal glucose release during hypoglycemia.

Effects of glimepiride and glyburide on glucose counterregulation and recovery from hypoglycemia.

Severe hypoglycemia, the most serious side effect of sulfonylurea therapy, has been reported to occur more frequently with glyburide than glimepiride. The present studies were undertaken to test the hypothesis that a differential effect on glucagon secretion may be involved. We performed hyperinsulinemic hypoglycemic (approximately 2.5 mmol/L) clamps in 16 healthy volunteers who received in randomized order placebo, glyburide (10 mg), and glimepiride (4 mg) just before beginning the insulin infusion and measured plasma glucagon, insulin, C-peptide, glucagon, epinephrine, cortisol, and growth hormone levels during the clamp and during a 3-hour recovery period after discontinuation of the insulin infusion. Neither sulfonylurea altered glucagon responses or those of other counterregulatory hormones (except cortisol) during the clamp. However, glyburide delayed plasma glucose recovery from hypoglycemia (plasma glucose at end of recovery period: control, 4.9 +/- 0.2 mmol/L; glyburide, 3.7 +/- 0.2 mmol/L; P = .0001; glimepiride, 4.5 +/- 0.2 mmol/L; P = .08). Despite lower plasma glucose levels, glyburide stimulated insulin secretion during this period (0.89 +/- 0.13 vs 1.47 +/- 0.15 pmol x kg(-1) x min(-1), control vs glyburide; P = .001), whereas glimepiride did not (P = .08). Short-term administration of glyburide or glimepiride did not alter glucagon responses during hypoglycemia. In contrast, during recovery from hypoglycemia, glyburide but not glimepiride inappropriately stimulates insulin secretion at low plasma glucose levels. This differential effect on insulin secretion may be an important factor in explaining why glyburide causes severe hypoglycemia more frequently than glimepiride.

Multiple defects in counterregulation of hypoglycemia in modestly advanced type 2 diabetes mellitus.

In type 2 diabetes mellitus (T2DM), little is known about hormonal responses to hypoglycemia. In particular, beta-cell responses to hypoglycemia have not been carefully investigated and potentially because of confounding factors or insufficient power, conflicting data have been obtained regarding growth hormone responses. We therefore compared hormonal responses including rates of insulin secretion during a 2-hour hyperinsulinemic hypoglycemic clamp in a relatively large number of nondiabetic (n=21) and moderately insulin-deficient subjects with T2DM (homeostasis model assessment of beta-cell function [HOMA-%B], 751+/-160 vs 1144+/-83 [pmol/L]/[mmol/L], P<.04) (n=14) matched for age, sex, and body mass index. Subjects with T2DM were excluded for antecedent hypoglycemia, and baseline glycemia was controlled by a variable infusion of insulin overnight. Although both groups of subjects had indistinguishable plasma glucose levels at baseline and virtually identical levels of plasma insulin and glucose throughout the hypoglycemic clamp, insulin secretion decreased more slowly in the subjects with T2DM. The time required for insulin secretion to decline to half its baseline level was markedly increased (38.9+/-4.9 vs 22.3+/-1.3 minutes [SD], P<.01), and insulin secretion decreased to a lesser extent (-0.79+/-0.17 vs -1.51+/-0.09 [pmol/L]/kg per minute, P<.002). Moreover, responses of glucagon (28.3+/-7.3 vs 52.8+/-7.0 ng/L, P<.05) and growth hormone (2.9+/-0.8 vs 6.3+/-0.9 ng/mL, P<.04) were reduced in the subjects with T2DM, whereas responses of epinephrine, norepinephrine, and cortisol were similar to those in nondiabetic subjects (all P>0.6). We conclude that multiple defects exist in hormonal responses to hypoglycemia in T2DM with moderate beta-cell failure. These include delayed and reduced decreases in insulin secretion, and impaired increases of plasma glucagon and growth hormone.

Fluctuation of serum basal insulin levels following single and multiple dosing of insulin glargine.

BACKGROUND: The large fluctuations in blood concentrations and activity observed with insulin therapies such as NPH insulin or insulin ultralente may result in hyper- or hypoglycemia. METHODS: We compared the fluctuations of these insulins with the long-acting basal insulin analog insulin glargine as a re-analysis of three Phase I studies: (I) glargine with NPH or ultralente [single-dose (0.4 IU/kg), randomized study in healthy volunteers (n = 36)]; (II) glargine or NPH [single-dose (0.3 IU/kg), randomized study in patients with diabetes mellitus Type 1 (DMT1) (n = 20)]; and (III) glargine (tailor-made dose) plus insulin lispro in DMT1 (n = 15 over 11 days). Percent deviation around average serum concentration over 24 h (PF24) was used to determine within-patient fluctuation and mean fluctuation value for each treatment group. RESULTS: Mean PF24 in healthy volunteers (Study I) was significantly lower with glargine (19.8%) than with NPH and ultralente (31.9% and 47.2%, respectively; both P < 0.001 vs. glargine). Similarly, about half the fluctuation observed with NPH (PF24 25.8%) was seen with glargine (PF24 14.2%; P < 0.001) in DMT1 (Study II). In ambulatory DMT1 patients receiving multiple glargine doses, PF24 values demonstrated that the same low fluctuations (PF24 20%) were retained throughout near-maintenance treatment (Study III). CONCLUSIONS: Glargine provided less diurnal fluctuation in serum insulin levels than NPH and ultralente in healthy volunteers and patients with DMT1. This lower fluctuation of glargine over NPH or ultralente can help to reduce hyper- or hypoglycemia risks associated with insulin therapy and accordingly encourage achievement of better blood glucose control.

Postprandial hyperglycemia and cardiovascular disease.

OBJECTIVE: To review the role of postprandial hyperglycemia in the development of type 2 diabetes mellitus and cardiovascular disease. METHODS: The pathogenic mechanisms involved in the deterioration of glucose tolerance are discussed, and findings from relevant epidemiologic and clinical interventional studies are presented. RESULTS: It is now well established that hyperglycemia is an independent risk factor for cardiovascular disease, with no apparent threshold. In clinical practice, glycemic exposure is measured by hemoglobin A1c levels. These values reflect the contribution of fasting and postprandial plasma glucose levels during the previous 2 to 3 months. Epidemiologic studies have indicated that, at hemoglobin A1c levels (5.5%) already associated with a substantially increased risk for cardiovascular mortality, fasting plasma glucose levels are generally normal. These observations implicate isolated postprandial hyperglycemia as a cardiovascular risk factor. Controlled interventional clinical trials have found that reduction of postprandial hyperglycemia decreases cardiovascular events or surrogates thereof. CONCLUSION: Postprandial hyperglycemia should be considered a cardiovascular risk factor similar to hypertension, hyperlipidemia, and smoking; accordingly, it should be monitored and treated.

Clinicians can help their patients control postprandial hyperglycemia as a means of reducing cardiovascular risk.

Cardiovascular disease is the leading cause of morbidity and mortality among patients with diabetes. Having diabetes is now recognized as conferring the same risk for cardiovascular disease as hyperlipidemia, hypertension, and smoking. HbA1c levels are the primary indicator of diabetes control and overall glycemic exposure. And recent research has pointed to postprandial hyperglycemia as conferring a greater risk of cardiovascular disease than elevated fasting plasma glucose levels. Unfortunately, clinicians sometimes forget that elevated HbA1c levels can arise from both fasting hyperglycemia and postprandial hyperglycemia. This is particularly important to remember when treating patients whose HbA1c levels may be higher than the desired target while fasting plasma glucose test results are within reference range. This article reviews the evidence supporting the view that postprandial hyperglycemia is a risk factor for cardiovascular disease and therefore should be controlled. Case studies are presented to aid clinicians in helping patients learn how to measure and control their postprandial glucose levels.

PRESERVE-beta: two-year efficacy and safety of initial combination therapy with nateglinide or glyburide plus metformin.

OBJECTIVE: To compare long-term efficacy and safety of initial combination therapy with nateglinide/metformin versus glyburide/metformin. RESEARCH DESIGN AND METHODS: We conducted a randomized, multicenter, double-masked, 2-year study of 428 drug-naïve patients with type 2 diabetes. Patients received 120 mg a.c. nateglinide or 1.25 mg q.d. glyburide plus 500 mg q.d. open-label metformin for the initial 4 weeks. During a subsequent 12-week titration period, glyburide and metformin were increased by 1.25- and 500-mg increments to maximum daily doses of 10 and 2,000 mg, respectively, if biweekly fasting plasma glucose (FPG) > or = 6.7 mmol/l. Nateglinide was not titrated. Blinding was maintained by use of matching placebo for nateglinide and glyburide. An 88-week monitoring period followed, during which HbA1c (A1C), FPG, and postprandial glucose excursions (PPGEs) during an oral glucose tolerance test were measured. RESULTS: In nateglinide/metformin-treated patients, mean A1C was 8.4% at baseline and 6.9% at week 104. In glyburide/metformin-treated patients, mean A1C was 8.3% at baseline and 6.8% at week 104 (P < 0.0001 vs. baseline for both treatments, NS between treatments). The deltaPPGE averaged -96 +/- 19 (P < 0.0001) and -57 +/- 22 mmol.l(-1).min(-1) (P < 0.05) in patients receiving nateglinide/metformin and glyburide/metformin, respectively, whereas deltaFPG was -1.6 +/- 0.2 (P < 0.0001) and -2.4 +/- 0.2 mmol/l (P < 0.0001) in patients receiving nateglinide/metformin and glyburide/metformin, respectively (P < 0.01 between groups). Thus, the two treatments achieved similar efficacy with differential effects on FPG versus PPGE. Hypoglycemia occurred in 8.2 and 17.7% of patients receiving nateglinide/metformin and glyburide/metformin, respectively. CONCLUSIONS: Similar good glycemic control can be maintained for 2 years with either treatment regimen, but nateglinide/metformin may represent a safer approach to initial combination therapy.

Role of the decrement in intraislet insulin for the glucagon response to hypoglycemia in humans.

OBJECTIVE: Animal and in vitro studies indicate that a decrease in beta-cell insulin secretion, and thus a decrease in tonic alpha-cell inhibition by intraislet insulin, may be an important factor for the increase in glucagon secretion during hypoglycemia. However, in humans this role of decreased intraislet insulin is still unclear. RESEARCH DESIGN AND METHODS: We studied glucagon responses to hypoglycemia in 14 nondiabetic subjects on two separate occasions. On both occasions, insulin was infused from 0 to 120 min to induce hypoglycemia. On one occasion, somatostatin was infused from -60 to 60 min to suppress insulin secretion, so that the decrement in intraislet insulin during the final 60 min of hypoglycemia would be reduced. On the other occasion, subjects received an infusion of normal saline instead of the somatostatin. RESULTS: During the 2nd h of the insulin infusion, when somatostatin or saline was no longer being infused, plasma glucose ( approximately 2.6 mmol/l) and insulin levels ( approximately 570 pmol/l) were comparable in both sets of experiments (both P > 0.4). In the saline experiments, insulin secretion remained unchanged from baseline (-90 to -60 min) before insulin infusion and decreased from 1.20 +/- 0.12 to 0.16 +/- 0.04 pmol . kg(-1) . min(-1) during insulin infusion (P < 0.001). However, in the somatostatin experiments, insulin secretion decreased from 1.18 +/- 0.12 pmol . kg(-1) . min(-1) at baseline to 0.25 +/- 0.09 pmol . kg(-1) . min(-1) before insulin infusion so that it did not decrease further during insulin infusion (-0.12 +/- 0.10 pmol . kg(-1) . min(-1), P = 0.26) indicating the complete lack of a decrement in intraislet insulin during hypoglycemia. This was associated with approximately 30% lower plasma glucagon concentrations (109 +/- 7 vs. 136 +/- 9 pg/ml, P < 0.006) and increments in plasma glucagon above baseline (41 +/- 8 vs. 67 +/- 11 pg/ml, P < 0.008) during the last 15 min of the hypoglycemic clamp. In contrast, increases in plasma growth hormone were approximately 70% greater during hypoglycemia after somatostatin infusion (P < 0.007), suggesting that to some extent the increases in plasma glucagon might have reflected a rebound in glucagon secretion. CONCLUSIONS: These results provide direct support for the intraislet insulin hypothesis in humans. However, the exact extent to which a decrement in intraislet insulin accounts for the glucagon responses to hypoglycemia remains to be established.

Use of inhaled insulin in a basal/bolus insulin regimen in type 1 diabetic subjects: a 6-month, randomized, comparative trial.

OBJECTIVE: Despite the demonstrated benefits of glycemic control, patient acceptance of basal/bolus insulin therapy for type 1 diabetes has been slow. We investigated whether a basal/bolus insulin regimen involving rapid-acting, dry powder, inhaled insulin could provide glycemic control comparable with a basal/bolus subcutaneous regimen. RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes (ages 12-65 years) received twice-daily subcutaneous NPH insulin and were randomized to premeal inhaled insulin (n = 163) or subcutaneous regular insulin (n = 165) for 6 months. RESULTS: Mean glycosylated hemoglobin (A1C) decreased comparably from baseline in the inhaled and subcutaneous insulin groups (-0.3 and -0.1%, respectively; adjusted difference -0.16% [CI -0.34 to 0.01]), with a similar percentage of subjects achieving A1C <7%. Although 2-h postprandial glucose reductions were comparable between the groups, fasting plasma glucose levels declined more in the inhaled than in the subcutaneous insulin group (adjusted difference -39.5 mg/dl [CI -57.5 to -21.6]). Inhaled insulin was associated with a lower overall hypoglycemia rate but higher severe hypoglycemia rate. The overall hypoglycemia rate (episodes/patient-month) was 9.3 (inhaled) vs. 9.9 (subcutaneous) (risk ratio [RR] 0.94 [CI 0.91-0.97]), and the severe hypoglycemia rate (episodes/100 patient-months) was 6.5 vs. 3.3 (RR 2.00 [CI 1.28-3.12]). Increased insulin antibody serum binding without associated clinical manifestations occurred in the inhaled insulin group. Pulmonary function between the groups was comparable, except for a decline in carbon monoxide-diffusing capacity in the inhaled insulin group without any clinical correlates. CONCLUSIONS: Inhaled insulin may provide an alternative for the management of type 1 diabetes as part of a basal/bolus strategy in patients who are unwilling or unable to use preprandial insulin injections.

Increasing the decrement in insulin secretion improves glucagon responses to hypoglycemia in advanced type 2 diabetes.

OBJECTIVE: In advanced beta-cell failure, counterregulatory glucagon responses may be impaired due to a reduced decrement in insulin secretion during the development of hypoglycemia. The present studies were therefore undertaken to test the hypothesis that these may be improved by increasing this decrement in insulin secretion. RESEARCH DESIGN AND METHODS: Twelve subjects with type 2 diabetes who have been insulin requiring were studied as a model of advanced beta-cell failure. Glucagon responses were examined during a 90-min hypoglycemic clamp (approximately 2.8 mmol/l) on two separate occasions. On one occasion, tolbutamide was infused for 2 h before the clamp so that the decrement in insulin secretion during the induction of hypoglycemia would be increased. On the other occasion, normal saline was infused as a control. RESULTS: Before the hypoglycemic clamp, infusion of tolbutamide increased insulin secretion approximately 1.9-fold (P < 0.001). However, during hypoglycemia, insulin secretion decreased to similar rates on both occasions (P = 0.31) so that its decrement was approximately twofold greater following the tolbutamide infusion (1.63 +/- 0.20 vs. 0.81 +/- 0.17 pmol x kg(-1) x min(-1), P < 0.001). This was associated with more than twofold-greater glucagon responses (42 +/- 11 vs. 19 +/- 8 ng/l, P < 0.002) during the hypoglycemic clamp but unaltered glucagon responses to intravenous arginine immediately thereafter (449 +/- 50 vs. 453 +/- 50 ng/l, P = 0.78). CONCLUSIONS: Increasing the decrement in insulin secretion during the development of hypoglycemia improves counterregulatory glucagon responses in advanced beta-cell failure. These findings further support the concept that the impaired counterregulatory glucagon responses in advanced beta-cell failure may at least partially be due to a reduced decrement in insulin secretion.

A potential important role of skeletal muscle in human counterregulation of hypoglycemia.

CONTEXT: During hypoglycemia, systemic glucose uptake (SGU) decreases and endogenous glucose release (EGR) increases. Skeletal muscle appears to be primarily responsible for the reduced SGU and may be important for the increased EGR by providing lactate for gluconeogenesis (GN). OBJECTIVE: The objective of the study was to test the hypothesis that reduced muscle glucose uptake and increased muscle lactate release both make major contributions to glucose counterregulation using systemic isotopic techniques in combination with forearm net balance measurements. SETTING: The study was conducted at the University of Giessen Clinical Research Center. PARTICIPANTS: Nine healthy volunteers participated in the study. INTERVENTION: A 2-h hyperinsulinemic euglycemic clamp (blood glucose approximately 4.4 mm) was followed by a 90-min hypoglycemic clamp (blood glucose approximately 2.6 mm). RESULTS: Compared with the euglycemic clamp, SGU decreased (21.0 +/- 2.0 vs. 29.6 +/- 1.8 micromol.kg body weight(-1).min(-1); P < 0.001), whereas EGR (11.2 +/- 1.7 vs. 4.9 +/- 1.3 micromol.kg body weight(-1) .min(-1); P < 0.003), arterial lactate concentrations (1051 +/- 162 vs. 907 +/- 115 microm; P < 0.02), systemic lactate release (23.5 +/- 0.9 vs. 17.1 +/- 0.9 micromol.kg body weight(-1).min(-1); P < 0.001), and lactate GN (4.50 +/- 0.60 vs. 2.74 +/- 0.30 micromol.kg body weight(-1).min(-1); P < 0.02) increased during hypoglycemia; the proportion of lactate used for GN remained unchanged (38 +/- 4 vs. 32 +/- 3%; P = 0.27). Whole-body muscle glucose uptake decreased approximately 50% during hypoglycemia (6.4 +/- 1.9 vs. 13.6 +/- 2.9 micromol.kg body weight(-1).min(-1); P < 0.001), which accounted for approximately 85% of the reduction of SGU. Whole-body muscle lactate release increased 6.6 +/- 1.6 micromol.kg body weight(-1). min(-1) (P < 0.01), which could have accounted for all the increase in systemic lactate release and, considering the proportion of lactate used for GN, contributed 1.4 +/- 0.4 micromol.kg body weight(-1).min(-1) (approximately 25%) to the increase in EGR. CONCLUSIONS: Reduced muscle glucose uptake and increased muscle lactate release both make major contributions to glucose counterregulation in humans.