Frank P. Kennedy

Insulin Dose-Response Characteristics for Suppression of Glycerol Release and Conversion to Glucose in Humans

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.

Malabsorptive procedures for severe obesity: comparison of pancreaticobiliary bypass and very very long limb Roux-en-Y gastric bypass

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 (WLGB) 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/m2 and 67 ±3 kg/m2), 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 WLGB 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/m2 and 42 ±2 kg/m2 in the PBB and WLGB groups, respectively. Hospital mortality was zero. Morbidity occurred in five patients after WLGB (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.

Recent developments in insulin delivery techniques : current status and future potential

SummaryAlthough 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.

Baseline Characteristics of Patients with Diabetes and Coronary Artery Disease Enrolled in the BARI 2D Trial

BACKGROUND 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). METHODS 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. RESULTS 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 cholesterol >or=100 mg/dL, 52% had blood pressure >130/80 mm Hg, and 56% had body mass index >or=30 kg/m(2). CONCLUSIONS 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.

Quantification of the glycolytic origin of plasma glycerol: Implications for the use of the rate of appearance of plasma glycerol as an index of lipolysis in vivo☆

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.

Relationship Between Autonomic Function and Progression of Renal Disease in Diabetic Proteinuria Clinical Correlations and Implications for Blood Pressure Control

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 readings < 140/90 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 pressure > 100 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 to < 95 mm Hg.

Optimisation of the management of patients with coronary heart disease and type 2 diabetes mellitus

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 β-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), β-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.

Association Between Albuminuria and Duration of Diabetes and Myocardial Dysfunction and Peripheral Arterial Disease Among Patients With Stable Coronary Artery Disease in the BARI 2D Study

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.

Subnormal pancreatic polypeptide and epinephrine responses to insulin-induced hypoglycemia identify patients with insulin-dependent diabetes mellitus predisposed to develop overt autonomic neuropathy.

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.

Autonomic function in type I diabetes mellitus complicated by nephropathy a cross-sectional analysis in the presymptomatic phase

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)