Search

Many hormones are secreted in a pulsatile fashion that is more efficient than continuous secretion when tested in vivo. A trial of multiple daily insulin doses with or without the addition of weekly pulsatile insulin infusion therapy was designed to determine if deterioration of renal and retinal function could be blunted. Sixty-five study subjects were evaluated prospectively in 7 centers. Thirty-six patients were randomly allocated to the infusion group and 29 to the standard therapy group. Mean serum creatinine was 1.6 mg/dL in both groups. Subjects were excluded if clearance was less than 30 mL/min. There were no significant differences between the groups with respect to age, duration of diabetes, sex distribution, glycohemoglobin, blood pressure, angiotensin-converting enzyme inhibitor use, proteinuria, or baseline diabetic retinopathy (DR) severity level (all eyes exhibited DR; 8 were deemed technically not amenable to evaluation). Progression of DR was noted in 31.6% of 57 patients (32.3% treated, 30.8% control; P = 1.0) with both eyes evaluable. For patients with 12 or more months of follow-up, 27.9% of 43 patients demonstrated progression of DR (32.0% treated, 22.2% control; P = .57). There were no significant differences between study groups with respect to progression or marked progression, nor was there any influence of duration of follow-up. Progression of DR was noted in 18.8% of 122 eyes that could be adequately evaluated (17.9% of 67 treated, 20% of 55 controls; P = .39). Serum creatinine increased to 1.7 mg/dL in the treatment group and to 1.9 mg/dL in the control group (P = .03). Statistically significant preservation of renal function by pulsatile insulin infusion was not matched by a statistically significant prevention of DR progression compared with standard diabetes care. Inadequate statistical power or duration of the study, or lack of further benefit of pulsatile insulin infusion on the retina in the presence of angiotensin-converting enzyme inhibition may be responsible.

OBJECTIVE To evaluate the effect of prior duration of diabetes, glycated hemoglobin level at study entry, and microalbuminuria or macroalbuminuria on the extent and severity of coronary artery disease (CAD) and peripheral arterial disease. PATIENTS AND METHODS We studied baseline characteristics of the 2368 participants of the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) study, a randomized clinical trial that evaluates treatment efficacy for patients with type 2 diabetes and angiographically documented stable CAD. Patients were enrolled from January 1, 2001, through March 31, 2005. Peripheral arterial disease was ascertained by an ankle-brachial index (ABI) of 0.9 or less, and extent of CAD was measured by presence of multivessel disease, a left ventricular ejection fraction (LVEF) of less than 50%, and myocardial jeopardy index. RESULTS Duration of diabetes of 20 or more years was associated with increased risk of ABI of 0.9 or less (odds ratio [OR], 1.54; 95% confidence interval [CI], 1.04-2.26), intermittent claudication (OR, 1.61; 95% CI, 1.10-2.35), and LVEF of less than 50% (OR, 2.03; 95% CI, 1.37-3.02). Microalbuminuria was associated with intermittent claudication (OR, 1.53; 95% CI, 1.16-2.02) and ABI of 0.9 or less (OR, 1.31; 95% CI, 0.98-1.75), whereas macroalbuminuria was associated with abnormal ABI, claudication, and LVEF of less than 50%. There was a significant association between diabetes duration and extent of CAD as manifested by number of coronary lesions, but no other significant associations were observed between duration of disease, glycated hemoglobin levels, or albumin-to-creatinine ratio and other manifestations of CAD. CONCLUSION Duration of diabetes and microalbuminuria or macroalbuminuria are important predictors of severity of peripheral arterial disease and left ventricular dysfunction in a cohort of patients selected for the presence of CAD.

Background.Research has shown less aggressive treatment and poorer control of cardiovascular disease (CVD) risk factors in women than men.Methods.We analyzed sex differences in pharmacotherapy strategies and attainment of goals for hemoglobin A1c (HbA1c), blood pressure (BP), and low density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes and established coronary artery disease enrolled into the BARI 2D trial.Results.Similar numbers of drugs were prescribed in both women and men. Women were less frequent on metformin or sulfonylurea and more likely to take insulin and to be on higher doses of hydroxymethylglutaryl-CoA reductase inhibitors (statins) than men. After adjusting for baseline differences and treatment prescribed, women were less likely to achieve goals for HbA1c (OR = 0.71, 95% CI 0.57, 0.88) and LDL-C (OR = 0.64, 95% CI 0.53, 0.78). More antihypertensives were prescribed to women, and yet BP ≤ 130/80 mmHg did not differ by sex.Conclusions.Women entering the BARI 2D trial were as aggressively treated with drugs as men. Despite equivalent treatment, women less frequently met targets for HbA1c and LDL-C. Our findings suggest that there may be sex differences in response to drug therapies used to treat diabetes, hypertension, and hyperlipidemia.

Type 2 diabetes mellitus is a prevalent disease in Westernised society, and more than 50% of individuals with diabetes mellitus die from cardiovascular causes. The underlying metabolic defect of type 2 diabetes mellitus is a combination of insulin resistance and decreased secretion of insulin by pancreatic beta-cells. Insulin resistance commonly precedes the onset of type 2 diabetes mellitus and is usually associated with a metabolic syndrome including hypertension, dyslipidaemia and obesity. Treatment of known cardiovascular risk factors, including hyperglycaemia, dyslipidaemia, hypertension and smoking, plays a key role in delaying the onset and progression of coronary heart disease (CHD) and other forms of atherosclerosis in patients with diabetes mellitus. Sulphonylureas should be used with caution in patients with CHD but aspirin (acetylsalicylic acid), beta-blockers and ACE inhibitors play an important role in the medical management of patients with established coronary artery disease and diabetes mellitus. Patients with diabetes mellitus represent a higher risk group of patients after both percutaneous and surgical coronary revascularisation and the decision regarding the choice of revascularisation procedure should take into account angiographic characteristics, clinical status and patient preference. Patients presenting with diabetes mellitus and acute myocardial infarction should be considered for reperfusion therapy with either urgent thrombolytic therapy or primary percutaneous coronary intervention.

The purpose of this study was to assess the effects of pulsatile intravenous insulin therapy (PIVIT) on the progression of diabetic nephropathy in patients with type 1 diabetes mellitus (DM). This 18-month multicenter, prospective, controlled study involved 49 type 1 DM patients with nephropathy who were following the Diabetes Control and Complications Trial (DCCT) intensive therapy (IT) regimen. Of these, 26 patients formed the control group (C), which continued on IT, while 23 patients formed the treatment group (T) and underwent, in addition to IT, weekly PIVIT. Blood pressure in all patients was maintained below 140/90 mm Hg on antihypertensive medication, preferentially using angiotensin-converting enzyme (ACE) inhibitors. All study patients were seen in the clinic weekly for 18 months, had monthly glycohemoglobin (HbA1c), and every 3 months, 24-hour urinary protein excretion and creatinine clearance (CrCl) determinations. The HbA1c levels declined from 8.61% +/- 0.33% to 7.68% +/- 0.31% (P = .0028) in the T group and from 9.13% +/- 0.36% to 8.19% +/- 0.33% (P = .0015) in the C group during the study period. CrCl declined significantly in both groups, as expected, but the rate of CrCl decline in the T group (2.21 +/- 1.62 mL/min/yr) was significantly less than in the C group (7.69 +/- 1.88 mL/min/yr, P = .0343). We conclude that when PIVIT is added to IT in type 1 DM patients with overt nephropathy, it appears to markedly reduce the progression of diabetic nephropathy. The effect appears independent of ACE inhibitor therapy, blood pressure, or glycemic control.

Objective To determine prospectively the results of Roux-en-Y gastric bypass (RYGB) used as the primary weight-reducing operation in patients with medically complicated ("morbid") obesity. The RYGB procedure combines the advantages of a restrictive physiology (pouch of 10 mL) and a "dumping physiology" for high-energy liquids without requiring an externally reinforced (banded) stoma. Patients and Methods Between April 1987 and December 1998, a total of 191 consecutive patients with morbid obesity (median weight, 138 kg [range, 91–240 kg]; median body mass index, 49 kg/m 2 [range, 36–74 kg/m 2 ]), all of whom had directly weight-related morbidity, underwent RYGB and prospective follow-up. Results Hospital mortality was 0.5% (1/191), and hospital morbidity occurred in 10.5% (20/191). Good longterm weight loss was achieved, and patients adapted well to the required new eating habits. The mean ± SD weight loss at 1 year after operation (113 patients) was 52±1 kg or 68% ±2% of initial excess body weight. By 3 years postoperatively (74 patients), weight loss was still 66% ±2% of excess body weight. Overall, 53 (72%) of 74 patients had achieved and maintained a weight loss of 50% or more of their preoperative excess body weight 3 years after the operation. In addition, only 1 (1%) of 98 patients had persistent postoperative vomiting 1 or more times per week. Conclusion We believe that RYGB is a safe, effective procedure for most patients with morbid obesity and thus may be the current procedure of choice in patients requiring bariatric surgery for morbid obesity.

The aim of this study was to determine the efficacy and safety of two malabsorptive procedures for severe obesity. Prospectively collected data from eight men and three women who underwent partial biliopancreatic bypass (PBB) and 19 men and seven women who underwent very very long limb Roux-en-Y gastric bypass (VVLGB) for superobesity (preoperative weight >225% above ideal body weight) were evaluated. Age (42 +/- 3 years and 40 +/- 2 years), body mass index (64 +/- 4 kg/m(2) and 67 +/- 3 kg/m(2)), and percentage of excess body weight (183% +/- 17% and 203% +/- 12%) were similar (mean +/- standard error of the mean). Median follow-up was 96 months (range 72 to 108 months) and 24 months (range 18 to 60 months) for the PBB and VVLGB groups, respectively. Weight loss expressed as percentage of excess body weight was 68% +/- 4% 2 years and 71% +/- 5% 4 years after PBB, and 53% +/- 7% 2 years and 57% +/- 5% 4 years after VVLGB. Current body mass indexes are 37 +/- 2 kg/m(2) and 42 +/- 2 kg/m(2) in the PBB and VVLGB groups, respectively. Hospital mortality was zero. Morbidity occurred in five patients after VVLGB (wound infection in four, wound seroma in one, and pulmonary embolus in one) and in two patients after PBB (abscess in two, anastomotic leak in one, and gastrointestinal bleeding in one). After PBB, one woman died of refractory liver failure 18 months postoperatively and two other patients developed metabolic bone disease. No such known complications have occurred to date after VVLGB. We conclude that VVLGB is safe and effective for clinically significant obesity, results in sustained weight loss, and improves quality of life.

The objective of this study was to test the relationship between neurologic and microvascular complications of type 1 diabetes mellitus. It was hypothesized that the mechanisms operative in autonomic dysfunction seen in diabetic patients with microangiopathy play a role in the rapidity of progression to renal failure. Twenty-six type 1 diabetic patients with proteinuria were studied with computerized monitoring of heart rate variation during timed ventilation, assumption of upright posture, and Valsalva maneuver and with 24-h ambulatory blood pressure monitoring at baseline. Renal function was evaluated over the ensuing 12 months of intensive insulin therapy. Blood pressure was treated so as to achieve consistent 24-h readings140/90 mm Hg. Angiotensin converting enzyme inhibitors were the preferred antihypertensive agents. Serial serum creatinine concentrations were compared using repeated measures analysis of variance. Over 12 months there were no significant serum creatinine changes for any autonomic test group with normal results at baseline. Groups with abnormal autonomic results at baseline demonstrated statistically significant increases in serum creatinine over 12 months compared to their baseline. Of the tests, Valsalva separated groups of patients with similar degrees of baseline renal impairment. Each of the sympathetic plus Valsalva combinations demonstrated a significant difference in progression of serum creatinine increase over 12 months. In each instance, if both sympathetic and Valsalva results were abnormal, there was a statistically significant increase in serum creatinine over 12 months when compared to groups in which one or both test results were normal. There is a relationship between autonomic function and the progression of renal dysfunction. The inability to vary the heart rate to a Valsalva maneuver identifies a degree of parasympathetic dysfunction that permits unopposed sympathetic tone, heralding more rapid renal destruction. A simple inexpensive bedside laboratory test discerned a relatively low-risk group of diabetic patients with proteinuria that demonstrated no deterioration in renal function over 12 months. When the Valsalva maneuver was markedly abnormal the presence of a mean arterial pressure100 mm Hg was associated with a greater likelihood of rapid renal deterioration. This group at higher risk of renal deterioration should undergo aggressive lowering of mean arterial blood pressure to95 mm Hg.

The purpose of this study was to determine the prevalence of parasympathetic and sympathetic autonomic dysfunction in long-standing type I diabetics with established nephropathy and to correlate autonomic function with cardiac risk factors. We used prospective analysis of heart rate variations to standardized testing and 24-hour blood pressure control prior to enrollment in a study utilizing various methods of intense diabetic control to prevent deterioration of kidney function. The settings were outpatient clinical research units. The patients were 42 type I diabetics with proteinuria (total urinary protein > or = 300 mg/day or urinary albumin > or = 100 mg/day) and creatinine clearance > or = 30 mL/min. Heart rate variation during respiratory cycles with change in posture from supine to upright, and during the Valsalva maneuver was recorded by a computerized method. Mean arterial blood pressure was recorded for 24 h by a computerized method. Heart rate variations in this group were abnormal during timed respiratory cycles in 26 of 40 patients (56%), during changes in posture in 15 of 40 patients (38%), and during Valsalva maneuver in 13 of 34 patients (38%) whose retinal disease permitted Valsalva testing. Blunted day/night mean arterial pressure ratios occurred in 18 of 41 (44%) patients and were more severe in men than in women (1.00 v 1.06, P < or = .05). Absence of deep tendon reflexes was associated with an increased incidence of both parasympathetic (respiratory rate variation) and sympathetic (postural rate variation) abnormalities (both P < or = .05). Loss of vibration sensation was not associated with autonomic functional abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to examine lipids, a major treatment parameter in those with diabetes and heart disease, the authors analyzed baseline data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. The study consisted of 2368 participants with type 2 diabetes and coronary artery disease from 49 sites in 6 countries (2295 provided lipid measurements). Fifty-nine percent of participants had a low-density lipoprotein (LDL) cholesterol level

Although single or multiple daily subcutaneous injections of insulin are the mainstay of insulin delivery techniques, several other methods of insulin delivery are now available or in development, including: (a) continuous subcutaneous insulin infusion by a wearable infusion pump; (b) total or segmental transplantation of a pancreas; (c) transplantation of isolated islet cells; (d) implantation of a programmable insulin pump; (e) oral, nasal, rectal and transdermal mechanisms of insulin delivery; (f) insulin analogues; (g) implantation of polymeric capsules which give continuous or time-pulsed release of insulin; and (h) implantation of a biohybrid artificial pancreas which uses encapsulated islets. Many of these methods of insulin delivery are aimed at achieving a more physiological means of delivery of the insulin, thus to improve glycaemic control and hopefully minimise the secondary complications of diabetes. Techniques of multiple insulin injections and continuous subcutaneous insulin infusion pumps are already in widespread use and are resulting in improved glycaemic control. With the recent increased use of pancreatic transplantation, the rule of establishing euglycaemia will be elucidated in the treatment and prevention of microvascular and macrovascular complications of diabetes mellitus. Despite these advances, the ideal delivery of insulin to patients has yet to be developed. Subcutaneous methods of insulin delivery do not precisely mimic physiological insulin needs and transplantation requires risky immunosuppression. However, the future does look bright as glucose sensors are developed and insulin analogues synthesised.

Background: Ursodeoxycholic acid (UDCA) is a therapeutic bile acid used in dissolution of gallstones and treatment of several cholestatic liver diseases. Results obtained from primary biliary cirrhosis patients treated with UDCA suggested that this agent exerts significant cholesterol-lowering effects and justifies evaluation in primary hypercholesterolemic patients without liver disease. Purpose of this study was to determine whether UDCA had potential to be an effective, safe cholesterol-lowering agent in primary type IIa or IIb hypercholesterolemia. Methods: This was a multicenter randomized, double blind, placebo-controlled trial. After a 6-week placebo lead-in period during which two qualifying lipid profiles were obtained, patients with a mean serum LDL-cholesterol (LDL-C) between 130 and 190 mg/dL, triglycerides 30 mg/dL were randomized to UDCA or matching placebo for 24 weeks. Results: Seven sites screened 200 patients with 134 patients meeting the entry criteria who were randomized to the two treatments. There were 125 patients meeting the efficacy evaluation criteria, 57 on UDCA and 68 on placebo. LDL-C change from weeks 0 to 24 showed no significant difference between groups. No significant differences in changes for total cholesterol, HDL-cholesterol and triglycerides were observed. Both groups had similar adverse event profiles. Conclusions: UDCA did not show intrinsic cholesterol-lowering properties and therefore is not a useful therapy in treating type IIa or type IIb hypercholesterolemic patients. UDCA was confirmed as a well tolerated and safe drug in this population.

Hypertension is common in patients with non-insulin-dependent diabetes mellitus and is also an early sign of diabetic nephropathy in those with insulin-dependent diabetes. Hypertension contributes to the progression of both macrovascular disease and nephropathy in patients with diabetes. Certain antihypertensive agents can adversely affect carbohydrate and lipid metabolism. Angiotensin-converting enzyme inhibitors and calcium channel blockers may slow the progression of renal complications in patients with diabetes. The pharmacologic approaches to treatment of hypertension in patients with diabetes potentially differ from those in nondiabetic persons. On the basis of a review of the recent literature related to antihypertensive therapy for patients with diabetes, we describe an empiric approach to treatment of hypertension in such patients. The proposed approach must be modified as new data from randomized clinical trials become available.

The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial was undertaken to determine whether early revascularization intervention is superior to deferred intervention in the presence of aggressive medical therapy and whether antidiabetes regimens targeting insulin sensitivity are more or less effective than regimens targeting insulin provision in reducing cardiovascular events among patients with type 2 diabetes mellitus and stable coronary artery disease (CAD).The BARI 2D trial is a National Institutes of Health-sponsored randomized clinical trial with a 2 x 2 factorial design. Between 2001 and 2005, 49 clinical sites in North America, South America, and Europe randomized 2,368 patients. At baseline, the trial collected data on clinical history, symptoms, and medications along with centralized evaluations of angiograms, electrocardiograms, and blood and urine specimens.Most of the BARI 2D patients were referred from the cardiac catheterization laboratory (54%) or cardiology clinic (27%). Of the randomized participants, 30% were women, 34% were minorities, 61% had angina, and 67% had multiregion CAD. Moreover, 29% had been treated with insulin, 58% had hemoglobin A(1c)7.0%, 41% had low-density lipoprotein cholesterolor=100 mg/dL, 52% had blood pressure130/80 mm Hg, and 56% had body mass indexor=30 kg/m(2).Baseline characteristics in BARI 2D are well balanced between the randomized treatment groups, and the clinical profile of the study cohort is representative of the target population. As a result, the BARI 2D clinical trial is in an excellent position to evaluate alternative treatment approaches for diabetes and CAD.

The impaired epinephrine and glucagon responses to hypoglycemia often found in patients with insulin-dependent diabetes mellitus (IDDM) may be due to autonomic neuropathy. Since the pancreatic polypeptide response to hypoglycemia is mediated by cholinergic mechanisms, we used this response as an indicator of autonomic neuropathy to determine whether deficient epinephrine and glucagon responses in IDDM could be ascribed to an autonomic defect. The relationships between pancreatic polypeptide, epinephrine, and glucagon responses during insulin-induced hypoglycemia were assessed in 18 patients with IDDM who had no overt evidence of autonomic neuropathy, including normal standard cardiovascular reflex tests, and 11 age-matched nondiabetic subjects. All of the diabetic patients had impaired glucagon responses [19 +/- 3 (SEM) vs. 96 +/- 11 pg/ml, peak increment, P less than 0.001]. Ten of the 18 diabetic patients had either impairment of plasma epinephrine or plasma pancreatic polypeptide responses or both to hypoglycemia. Moreover, pancreatic polypeptide responses were significantly correlated with epinephrine responses (r = 0.53, P less than 0.003). There was no association between the plasma glucagon response and the epinephrine (r = 0.02, NS), norepinephrine (r = 0.03, NS), or pancreatic polypeptide (r = 0.35, NS) response. Last, there was no correlation between the plasma hormone responses and the cardiovascular reflex test results. Therefore, the association of impaired plasma pancreatic polypeptide responses with impaired plasma epinephrine responses suggests that the impaired epinephrine responses are due to autonomic neuropathy, whereas the dissociation of plasma glucagon responses with both plasma pancreatic polypeptide and epinephrine responses suggests that the impaired pancreatic alpha-cell response to hypoglycemia is not due to autonomic neuropathy. In addition, the plasma pancreatic polypeptide and epinephrine responses to hypoglycemia appear to be an earlier indicator of underlying autonomic dysfunction than standard cardiovascular reflex tests. Thus, the responses of plasma pancreatic polypeptide and epinephrine to insulin-induced hypoglycemia may be a useful test for the identification of early autonomic neuropathy in IDDM.

• We reviewed the clinical characteristics of 10 patients with thyrotoxic periodic paralysis. In these patients, a relatively uniform group of young men, the periodic paralysis developed nearly concurrently with the onset of hyperthyroidism. The attacks were precipitated most frequently by rest and by exercise and, occasionally, by ingestion of a large carbohydrate load. In each patient, the paralysis resolved on return of euthyroidism. The approximate incidence rate for thyrotoxic periodic paralysis in our largely white North American patient population (all hyperthyroidism cases) ranged from 0.1% to 0.2%, which is one tenth the rate reported for Oriental populations. In 7 patients, electrodiagnostic testing revealed characteristic changes in compound muscle action potential amplitude in response to exercise of the muscle being tested. (Arch Intern Med. 1989;149:2597-2600)

To compare the dose-response characteristics for suppression of lipolysis and suppression of glucose production by insulin, 13 normal nonobese individuals were infused with insulin at rates of 0.1, 0.2, 0.4, 0.8, and 1.6 mU · kg−1 · min−1 while normoglycemia was maintained with the glucose clamp technique. Glucose appearance and glycerol appearance (taken as index of lipolysis) were measured isotopically with simultaneous infusions of 3-[3H]glucose and U-[14C]glycerol. Baseline glucose and glycerol rates of appearance were 14 ± 0.5 and 1.7 ± 0.2 (μmol · kg−1 · min−1, respectively. Approximately 3% of plasma glucose originated from glycerol, and this accounted for ∼50% of glycerol disposal. During the insulin infusions, arterial insulin (basal, 9.8 ± 0.6 μU/ml) increased to 14 ± 0.5, 20 ± 0.5, 31 ± 1, 58 ± 2, and 104 ± 6 (μU/ml; calculated portal venous insulin (basal, 24 ± 2 μU/ml) increased to 26 ± 1, 32 ± 3, 70 ± 4, and 115 ± 6 JJLU ml. The rate of glucose appearance was suppressed 100%, whereas the rate of appearance of glycerol was maximally suppressed only 85%. Nevertheless, the insulin concentration that produced half-maximal suppression of glucose appearance was twice as great as that required for half-maximal suppression of glycerol appearance (26 ± 2 vs. 13 ± 2 μU/ml, P < .001). Insulin decreased both the absolute rate of glycerol conversion to plasma glucose and the percent of glycerol disposal appearing in plasma glucose (both P < .001). These results indicate that in normal humans the suppression of lipolysis is more sensitive to insulin than is the suppression of hepatic glucose production and that in addition to reducing glycerol availability, insulin suppresses glycerol incorporation into plasma glucose by another (presumably hepatic) mechanism.

Bay-m-1099, a new alpha-glucosidase inhibitor, was given along with insulin immediately before standard breakfasts, lunches and dinners to nine insulin-dependent diabetic patients to determine whether this combination therapy would produce postprandial glycemic control comparable to that achieved when insulin alone was administered 30 min prior to eating. To avoid potential hypoglycemia, 20% less insulin (0.12 vs. 0.15 U/kg) was given with Bay-m-1099. Despite plasma free insulin concentrations which were less than those observed when insulin alone was given (9.4 +/- 1.0 vs. 12.8 +/- 1.6 microU/ml/min, area under curves for all meals), postprandial hyperglycemia (area under curve) was not significantly different (P greater than 0.1) when insulin plus Bay-m-1099 was administered immediately before each meal (124 +/- 26 mg/ml/min) than when insulin was administered 30 min before each meal (113 +/- 17 mg/ml/min). Thus, the combination of immediate preprandial administration of an alpha-glucosidase inhibitor along with insulin resulted in glycemic control comparable to that achieved when more insulin was taken 30 min prior to eating. We conclude that use of alpha-glucosidase inhibitors could lessen the inconvenience of intensive insulin regimens by permitting patients to take their insulin immediately before eating and thus result in greater patient compliance.

Retardation of meal carbohydrate absorption by inhibition of starch degradation improves glucose tolerance in normal and diabetic humans. To determine the effects of Bay-m-1099, a new alpha-glucosidase inhibitor, on insulin requirements and prandial glucose tolerance in patients with insulin-dependent diabetes mellitus (IDDM), plasma glucose, triglyceride, and free insulin concentrations were measured after ingestion of a standard breakfast, lunch, and dinner in nine patients with IDDM in a single-blind, randomized, crossover design. A 20% reduction in insulin was given 30 minutes before the meals when the subjects received Bay-m-1099 (50 mg). This resulted in the AUC for plasma insulin to be significantly less with Bay-m-1099 (AUC, 8.2 +/- 1.3 vs. 12.8 +/- 1.6 microU/ml/min with placebo; P less than 0.01). Despite this reduction in plasma insulin levels, postprandial plasma glucose concentrations were reduced for the breakfast (73 +/- 15 vs. 112 +/- 14 mg/dl/min with placebo; P less than 0.01) and dinner (23 +/- 8 vs. 4 +/- 1 mg/dl/min with placebo; P less than 0.05) meal with Bay-m-1099. Bay-m-1099 did not affect postprandial plasma triglycerides and was well tolerated, the major side effect being flatulence (4/9) and mild diarrhea (4/9). We conclude that inhibition of intestinal alpha-glucosidases by Bay-m-1099 in IDDM reduces meal insulin requirements by at least 20% and that such an agent could be useful in the management of diabetes mellitus by reducing hyperinsulinemia.

To assess whether plasma glycerol could be directly derived from plasma glucose, nine postabsorptive dogs were infused with [U-14C] glucose and [2-3H] glycerol to measure the rates of appearance of plasma glucose and glycerol and the conversion of plasma glucose to glycerol before (basal) and after two hours of infusion of glucose (45 mumol/kg/min). Basally (plasma glucose 4.9 +/- 0.2 mmol/L; plasma insulin 5.9 +/- 0.2 microU/mL), rates of appearance of plasma glucose and glycerol were 20 +/- 2 and 5.9 +/- 1.3 mumol/kg/min, respectively, and 1.6 +/- 0.6% of plasma glycerol was derived from plasma glucose. After glucose infusion (plasma glucose 9.1 +/- 0.7 mmol/L; plasma insulin 21.1 +/- 1.9 microU/mL), the rate of appearance of plasma glycerol decreased 80% to 1.1 +/- 0.3 mumol/kg/min and the percent of plasma glycerol from glucose increased significantly to 6.9 +/- 2.9. However, the absolute rate of conversion of glucose to glycerol did not change (0.09 +/- 0.03 v 0.07 +/- 0.03 mumol/kg/min). We conclude that even under conditions of stimulated glycolysis and inhibited lipolysis, only a small amount of plasma glycerol is derived from plasma glucose. Thus, rates of appearance of plasma glycerol can be used as a measure of rates of overall lipolysis in vivo.

Sixteen patients with insulin-dependent diabetes mellitus with no current evidence of autonomic dysfunction underwent an insulin tolerance test during which plasma pancreatic polypeptide and epinephrine responses were determined. Compared to 11 age- and weight-matched nondiabetic volunteers, 9 diabetic subjects had subnormal plasma pancreatic polypeptide responses (n = 6) or plasma epinephrine responses (n - 8). When autonomic function was reassessed 2 to 3 years later by standard cardiovascular reflex tests and clinical examination, 8 of 9 diabetic subjects with subnormal hormonal responses to hypoglycemia developed either abnormal cardiovascular reflexes (6 of 9) or overt symptoms consistent with diabetic autonomic neuropathy (6 of 9), whereas none of the subjects with previously normal plasma pancreatic polypeptide and epinephrine responses did (P less than 0.01). Diminished pancreatic polypeptide and epinephrine responses to hypoglycemia can predict the development of overt autonomic neuropathy in patients with insulin-dependent diabetes mellitus; identification of patients with a predilection to develop autonomic neuropathy may permit earlier treatment.

L363,586 (now referred to as MK-678) is a cyclic hexapeptide analog of somatostatin. This compound, whose amino acid sequence is shown in Figure 1, was developed by chemists at Merck, Sharp and Dohme Research laboratories on the basis of modeling of the active site of the somatostatin molecule in a project which involved the synthesis of more than 150 analogs (1).