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 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.

Effects of pulsatile intravenous insulin therapy on the progression of diabetic nephropathy.

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.

Prospective evaluation of Roux-en-Y gastric bypass as primary operation for medically complicated obesity.

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/m2 [range, 36-74 kg/m2]), 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 long-term 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 bariatrics++ surgery for morbid obesity.

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 (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.

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.

A practical guideline for management of hypertension in patients with diabetes.

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.

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)

Recent developments in insulin delivery techniques. Current status and future potential.

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.

Thyrotoxic periodic paralysis. Report of 10 cases and review of electromyographic findings.

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.

Alpha-glucosidase inhibition and timing of preprandial insulin in patients with insulin-dependent diabetes mellitus (IDDM).

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.

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.

Effect of internalization and degradation of insulin on rat adipocyte insulin receptor binding kinetics.

We have assessed the influence of nondisplaceable (internalized) insulin and insulin degradation during binding reactions at 37 degrees C on the numbers and affinities of insulin binding sites on isolated rat adipocytes. Corrections for nondisplaceable insulin caused a 33% reduction in the number of the high affinity sites (p less than 0.01) and a 24% reduction (p less than 0.01) in the number of the low affinity sites which was associated with a 20% increase (p less than 0.01) in affinity when a two-site model was applied. With a one-site model, the number of insulin receptors decreased by approximately 33% (p less than 0.01), but the affinity did not change. These results indicate that the internalization and degradation of insulin that occurs during the binding reaction can significantly affect the estimation of insulin binding kinetics. Potential variations in internalization and degradation of insulin by cells obtained under various physiological or pathologic conditions should, therefore, be taken into consideration in the interpretation of insulin binding data.

Non-beta-cell islet abnormalities in noninsulin-dependent diabetes mellitus.

Although there are abnormalities in the function of pancreatic alpha, delta, and PP cells in NIDDM, only in the case of the glucagon-secreting alpha cells is there sufficient evidence to indicate that these abnormalities may be metabolically important. But the cause of abnormal glucagon secretion remains to be established. Studies of delta-cell secretion have been hampered by the inability to determine the source of circulating somatostatin-like immunoreactivity and the failure to distinguish between the potential molecular species being measured. Pancreatic polypeptide remains a hormone in search of a metabolic function; the main use of its measurement may be in the study of parasympathetic nervous system function in NIDDM.

A new alpha-glucosidase inhibitor (Bay-m-1099) reduces insulin requirements with meals in insulin-dependent diabetes mellitus.

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.

The effect of two new alpha-glucosidase inhibitors on metabolic responses to a mixed meal in normal volunteers.

1. alpha-Glucosidase inhibitors delay carbohydrate absorption and have been proposed as adjunctive therapy for diabetes mellitus. 2. To determine the effects of two new alpha-glucosidase inhibitors, Bay-m-1099 and Bay-o-1248, on meal carbohydrate and lipid tolerance, plasma glucose, insulin and triglyceride levels were measured at 15-60 min intervals over 12 h after ingestion of a standard breakfast, lunch and dinner of identical composition in 31 normal volunteers. 3. The volunteers were randomized to receive either Bay-m-1099 (50 or 25 mg) or placebo prior to each meal, or the single administration of Bay-o-1248 (20 or 10 mg) or placebo prior to breakfast. 4. Only Bay-m-1099 at the 50 mg dose reduced significantly the postprandial increase in plasma insulin levels after each meal when compared with placebo (25, 36, 54% at breakfast, lunch, and dinner, respectively; P less than 0.05). Both drugs were well tolerated, with side effects limited to complaints of flatulence. 5. Thus, with the dosage schedule employed, Bay-m-1099, but not Bay-o-1248, significantly reduced postprandial increments in plasma insulin.

The significance of impaired pancreatic polypeptide and epinephrine responses to hypoglycemia in patients with insulin-dependent diabetes mellitus.

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.

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 X kg-1 X 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 mumol X kg-1 X min-1, respectively. Approximately 3% of plasma glucose originated from glycerol, and this accounted for approximately 50% of glycerol disposal. During the insulin infusions, arterial insulin (basal, 9.8 +/- 0.6 microU/ml) increased to 14 +/- 0.5, 20 +/- 0.5, 31 +/- 1, 58 +/- 2, and 104 +/- 6 microU/ml; calculated portal venous insulin (basal, 24 +/- 2 microU/ml) increased to 26 +/- 1, 32 +/- 3, 70 +/- 4, and 115 +/- 6 microU/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 microU/ml, P less than .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 less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)