Harry Shamoon

Hypoglycemia in Diabetes

Iatrogenic hypoglycemia causes recurrent morbidity in most people with type 1 diabetes and many with type 2 diabetes, and it is sometimes fatal. The barrier of hypoglycemia generally precludes maintenance of euglycemia over a lifetime of diabetes and thus precludes full realization of euglycemias long-term benefits. While the clinical presentation is often characteristic, particularly for the experienced individual with diabetes, the neurogenic and neuroglycopenic symptoms of hypoglycemia are nonspecific and relatively insensitive; therefore, many episodes are not recognized. Hypoglycemia can result from exogenous or endogenous insulin excess alone. However, iatrogenic hypoglycemia is typically the result of the interplay of absolute or relative insulin excess and compromised glucose counterregulation in type 1 and advanced type 2 diabetes. Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine stand high in the hierarchy of redundant glucose counterregulatory factors that normally prevent or rapidly correct hypoglycemia. In insulin-deficient diabetes (exogenous) insulin levels do not decrease as glucose levels fall, and the combination of deficient glucagon and epinephrine responses causes defective glucose counterregulation. Reduced sympathoadrenal responses cause hypoglycemia unawareness. The concept of hypoglycemia-associated autonomic failure in diabetes posits that recent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal (including epinephrine) and the resulting neurogenic responses to lower plasma glucose concentrations, antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. Thus, short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in most affected patients. The clinical approach to minimizing hypoglycemia while improving glycemic control includes 1) addressing the issue, 2) applying the principles of aggressive glycemic therapy, including flexible and individualized drug regimens, and 3) considering the risk factors for iatrogenic hypoglycemia. The latter include factors that result in absolute or relative insulin excess: drug dose, timing, and type; patterns of food ingestion and exercise; interactions with alcohol and other drugs; and altered sensitivity to or clearance of insulin. They also include factors that are clinical surrogates of compromised glucose counterregulation: endogenous insulin deficiency; history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se, as evidenced by lower HbA(1c) levels, lower glycemic goals, or both. In a patient with hypoglycemia unawareness (which implies recurrent hypoglycemia) a 2- to 3-week period of scrupulous avoidance of hypoglycemia is advisable. Pending the prevention and cure of diabetes or the development of methods that provide glucose-regulated insulin replacement or secretion, we need to learn to replace insulin in a much more physiological fashion, to prevent, correct, or compensate for compromised glucose counterregulation, or both if we are to achieve near-euglycemia safely in most people with diabetes.

Reliability of blood glucose monitoring by patients with diabetes mellitus

Nineteen patients with insulin-dependent diabetes mellitus were evaluated for overall reliability of self-generated data from capillary blood glucose monitoring. For a period of 12 to 14 days, standard reflectance meters used by these subjects were replaced by meters internally modified with memory chips capable of storing all glucose readings by date and time. The subjects were not aware of this modification and were instructed to continue to test capillary blood glucose as they had been and to continue their practice of recording the meter readings in a logbook. To assess reliability of patient-generated data as recorded in the logbook, the addition, deletion, and alteration of test results were determined. A significantly lower (p less than 0.0001) mean blood glucose level was reported in the logbooks than recorded in the memory reflectance meters. Differences in logbooks and memory reflectance meters ranged from 0 to 109 mg/dl. Three fourths of the subjects had reported lower than actual mean blood glucose values. Under-reporting, or omission of memory reflectance meter readings, averaged 10 percent, whereas over-reporting or addition of phantom values averaged 40 percent. An average of 26 percent of the logbook entries were not identical to memory reflectance meter values determined at the corresponding time. Two thirds of the subjects had reported values in such a manner as to obscure hyper- and hypoglycemia, leading to misleading clinical impressions about the fluctuation in metabolic control. Previous glycemic control, patterns of logbook recording, or visits to the clinic were not found to be predictive of the reliability of patient self-monitoring regimens.

Psychological and Social Correlates of Glycemic Control

Eighty-four persons with insulin-dependent diabetes participated in this study to determine whether glycemic control was related to personality, anxiety, depression, and/or quality of life. The subjects were placed on either a conventional treatment regimen consisting of one to two injections of mixed short and intermediate-acting insulin, with urine testing or an intensive treatment regimen consisting of two or more injections of mixed insulins, with self-monitoring of blood glucose. Personality was found to have no relationship to level of glycemic control either at the beginning of the study or at any point during the study. In contrast, anxiety, depression, and quality of life showed a significant relationship to metabolic control at entry and throughout the study period. Lower anxiety and depression scores and better quality of life scores were recorded for those subjects in good control (HbA1 < 8.9%) when compared with those in average control (HbA1 9.0–11.9%) and those in poor control (HbA1 > 11.9%) at entry (P = 0.01). At each point during the study the difference between those in good control and those in poor controlin terms of anxiety, depression, and quality of life was significant (P = 0.02). Change in glycemic control was found to account for up to 20% of the between-patient variability for these psychosocial parameters.

Efficacy, Safety, and Dose-Response Characteristics of Glipizide Gastrointestinal Therapeutic System on Glycemic Control and Insulin Secretion in NIDDM: Results of two multicenter, randomized, placebo-controlled clinical trials

OBJECTIVE To investigate the efficacy, safety, and dose-response characteristics of an extended-release preparation of glipizide using the gastrointestinal therapeutic system (GITS) on plasma glucose, glycosylated hemoglobin (HbA1c), and insulin secretion to a liquid-mixed meal in NIDDM patients. RESEARCH DESIGN AND METHODS Two prospective, randomized, double-blind, placebo-controlled, multicenter clinical trials were performed in 22 sites and 347 patients with NIDDM (aged 59 ± 0.6 years; BMI, 29 ± 0.3 kg/m2; known diabetes duration, 8 ± 0.4 years) were studied. Each clinical trial had a duration of 16 weeks with a 1-week washout, 3-week single-blind placebo phase, 4-week titration to a fixed dose, and 8-week maintenance phase at the assigned dose. In the first trial, once-daily doses of 5, 20, 40, or 60 mg glipizide GITS were compared with placebo in 143 patients. In the second trial, doses of 5, 10, 15, or 20 mg of glipizide GITS were compared with placebo in 204 patients. HbA1c, fasting plasma glucose (FPG), insulin, C-peptide, and glipizide levels were determined at regular intervals throughout the study. Postprandial plasma glucose (PPG), insulin, and C-peptide also were determined at 1 and 2 h after a mixed meal (Sustacal). RESULTS All doses of glipizide GITS in both trials produced significant reductions from placebo in FPG (range −57 to −74 mg/dl) and HbA1c (range −1.50 to −1.82%). Pharmacodynamic analysis indicated a significant relationship between plasma glipizide concentration and reduction in FPG and HbA1c over a dose range of 5–60 mg, with maximal efficacy achieved at a dose of 20 mg for FPG and at 5 mg for HbA1c. PPG levels were significantly lower, and both postprandial insulin and C-peptide levels significantly higher in patients treated with glipizide GITS compared with placebo. The percent reduction in FPG was comparable across patients with diverse demographic and clinical characteristics, including those with entry FPG ≥ 250 mg/dl, resulting in greater absolute decreases in FPG and HbA1c in patients with the most severe hyperglycemia. Despite the forced titration to a randomly assigned dose, only 11 patients in both studies discontinued therapy because of hypoglycemia. Glipizide GITS did not alter lipids levels or produce weight gain. CONCLUSIONS The once-daily glipizide GITS 1) lowered HbA1c, FPG, and PPG over a dose range of 5–60 mg, 2) was maximally effective at 5 mg (using HbA1c) or 20 mg (using FPG) based on pharmacokinetic and pharmacodynamic relationships, 3) maintained its effectiveness in poorly controlled patients (those with entry FPG ≥ 250 mg/dl), 4) was safe and well tolerated in a wide variety of patients with NIDDM, and 5) did not produce weight gain or adversely affect lipids.

Regulation of endogenous glucose production by glucose per se is impaired in type 2 diabetes mellitus.

We examined the ability of an equivalent increase in circulating glucose concentrations to inhibit endogenous glucose production (EGP) and to stimulate glucose metabolism in patients with Type 2 diabetes mellitus (DM2). Somatostatin was infused in the presence of basal replacements of glucoregulatory hormones and plasma glucose was maintained either at 90 or 180 mg/dl. Overnight low-dose insulin was used to normalize the plasma glucose levels in DM2 before initiation of the study protocol. In the presence of identical and constant plasma insulin, glucagon, and growth hormone concentrations, a doubling of the plasma glucose levels inhibited EGP by 42% and stimulated peripheral glucose uptake by 69% in nondiabetic subjects. However, the same increment in the plasma glucose concentrations failed to lower EGP, and stimulated glucose uptake by only 49% in patients with DM2. The rate of glucose infusion required to maintain the same hyperglycemic plateau was 58% lower in DM2 than in nondiabetic individuals. Despite diminished rates of total glucose uptake during hyperglycemia, the ability of glucose per se (at basal insulin) to stimulate whole body glycogen synthesis (glucose uptake minus glycolysis) was comparable in DM2 and in nondiabetic subjects. To examine the mechanisms responsible for the lack of inhibition of EGP by hyperglycemia in DM2 we also assessed the rates of total glucose output (TGO), i.e., flux through glucose-6-phosphatase, and the rate of glucose cycling in a subgroup of the study subjects. In the nondiabetic group, hyperglycemia inhibited TGO by 35%, while glucose cycling did not change significantly. In DM2, neither TGO or glucose cycling was affected by hyperglycemia. The lack of increase in glucose cycling in the face of a doubling in circulating glucose concentrations suggested that hyperglycemia at basal insulin inhibits glucose-6-phosphatase activity in vivo. Conversely, the lack of increase in glucose cycling in the presence of hyperglycemia and unchanged TGO suggest that the increase in the plasma glucose concentration failed to enhance the flux through glucokinase in DM2. In summary, both lack of inhibition of EGP and diminished stimulation of glucose uptake contribute to impaired glucose effectiveness in DM2. The abilities of glucose at basal insulin to both increase the flux through glucokinase and to inhibit the flux through glucose-6-phosphatase are impaired in DM2. Conversely, glycogen synthesis is exquisitely sensitive to changes in plasma glucose in patients with DM2.

Self-Monitoring of Capillary Blood Glucose: Changing the Performance of Individuals with Diabetes

Standard reflectance meters were modified by the addition of memory chips capable of storing 440 glucose determinations with corresponding time and date. These modified reflectance meters (MR) were given to 20 individuals with type I diabetes in an effort to determine the level of reliability and accuracy they could achieve on a self-monitoring regimen. During a 6-wk period these subjects measured their capillary blood glucose and recorded the results in a logbook (LB). At 2-wk intervals they visited the clinic. Data from the MR was offloaded onto an Apple IIe microcomputer (Apple Computer, Inc., Cupertino, California) and presented to the subjects in a graphic format, depicting the level of metabolic control over the previous 2 wk. The performance of subjects for the 6-wk period showed that they averaged 7 omissions from the LB for every 100 MR recordings; 1 added value in the LB for every 200 MR recordings; and 1 error in accurately copying the test value for every 100 determinations. In comparison with subjects who participated in an earlier study in which they were unaware of the memory function of the reflectance meter, performance during the current study improved in all categories. It was also observed that consistency in reliable and accurate record keeping did not diminish throughout the study period. Despite these positive changes in performance, no alteration in glycemic control was found.

Effect of Propranolol on Delayed Glucose Recovery After Insulin-induced Hypoglycemia in Normal and Diabetic Subjects

In order to evaluate the influence of β-adrenergic blockade on recovery from insulin-induced hypoglycemia, we compared the effect of saline or propranolol infusion during concomitant hypoglycemia in normal and type I diabetic persons. The diabetic subjects were initially rendered euglycemic with a basal insulin infusion. Glucose turnover was measured using [3-3H]glucose tracer. Propranolol caused a small but significant delay in glucose recoveryin normal subjects, with plasma glucose only 80% of the values seen during saline infusion 1 h after hypoglycemia (P < 0.005). This delay was caused by a 70% reduction in the rebound glucose output, which was responsible for posthypoglycemic recovery. In the diabetic subjects, glucose recovery was significantly delayed as compared with that in normalpersons, even in the absence of propranolol, and associated with reduced secretion of epinephrine and glucagon. Moreover, the addition of propranolol caused a further 50% reduction in glucose recovery such that plasma glucose remained below 50 mg/dl for 3 h. In contrast to normals, propranolol did not inhibit the already blunted rebound in glucose output. However, propranolol prevented the decline in glucose utilization that occurred when saline alone was infused. During saline infusion, glucose uptake was at basal rates by 60 min whereas, during propranolol administration, glucose uptake remained above baseline until 180 min (P < 0.01). Thus, propranolol may interfere with glucose recovery after insulin-induced hypoglycemia in diabetic patients by blocking epinephrines inhibition of glucose utilization whereas, in normals, propranolols effect is largely accounted for by blockade of epinephrineinduced hepatic glucose production.

Diabetes Care Needs of Hispanic Patients Treated at Inner-City Neighborhood Clinics in New York City

The charts of 254 Hispanic patients were selected from a sample of 321 patients with diabetes in four urban clinics that received federal funding to provide medical care in underserved communities. A standardized chart-audit protocol was used to assess the process of healthcare delivery and the presence of diabetes-associated comorbidities and complications in patients. Inconsistent recognition of obesity (11% identified vs 59% present), hyperlipidemia (17% identified vs 69% present), and renal dysfunction (3.5% identified vs 16% present) was evident on chart review. We also found inadequate compliance with current recommendations for diabetes care with respect to routine health screenings for diabetes-related complications, recognition of comorbid diagnoses, and referral of patients for recommended specialty consultations. Issues specific to the varied Hispanic populations may need to be considered to improve the delivery of diabetes care for the growing Hispanic population with diabetes.

Quality Assurance for Blood Glucose Monitoring in Health-Care Facilities

Objective To describe the practice of quality assurance (QA) for capillary blood glucose monitoring (CBGM) in health-care facilities. Research Design and Methods Descriptive survey data were collected from a purposive sample of 378 health-care providers, who use CBGM and direct CBGM QA programs, from acute- and chronic-care facilities in 47 states. Subjects completed a 36-item multiple-choice survey about QA practices for CBGM by providers. Results Only 53.4% of respondents reported a multidisciplinary advisory group to assist in decision making for the CBGM program. Almost one-third reported no clinical laboratory involvement in their QA program. Over 70% of respondents reported inclusion of all clinical areas in the CBGM program. Comparison of results of the same patient sample by laboratory reference method and CBGM system was done routinely by only 43.6% of respondents. Scheduled proficiency testing was reported by 33.4%. Only 5.8% of respondents reported the coexistence of a CBGM advisory group, full participation of the laboratory, and quarterly proficiency testing. Over 50% of respondents reported a patient charge for CBGM. Conclusions When survey results are compared with regulatory and accreditation standards, it is evident that a wide gap exists. Resources to bridge this gap may be scarce in many facilities. Further research is needed to determine minimal QA standards for CBGM that provide for optimal patient outcomes.

Opioid Receptor Blockade Prevents Exercise-Associated Autonomic Failure in Humans

Hypoglycemia and exercise both induce the release of β-endorphin, which plays an important role in the modulation of the autonomic response during subsequent events. Because opioid receptor (OR) blockade during antecedent hypoglycemia has been shown to prevent hypoglycemia-associated autonomic failure, we hypothesized that OR blockade during exercise would prevent exercise-associated autonomic failure (EAAF). We studied 8 healthy subjects on 2 consecutive days, each of whom participated in three different studies in random order. The protocol on day 1 involved one of the following: 1) two 90-min hyperinsulinemic-euglycemic clamps plus naloxone infusion (control); 2) two 90-min hyperinsulinemic-euglycemic clamps with exercise at 60% Vo2max, plus naloxone infusion (N+); or 3) same protocol as in the N+ group, but with saline infusion only (N−). On day 2, all were studied with stepped hyperinsulinemic-hypoglycemic clamps, using hormone concentrations and glucose turnover as indicators of hypoglycemia counterregulation. Compared with control, N− studies resulted in significantly blunted epinephrine and norepinephrine responses to subsequent hypoglycemia. Conversely, the N+ group exhibited unimpaired hypoglycemia counterregulation, characterized by appropriate increases in epinephrine, norepinephrine, and endogenous glucose production. Thus, OR blockade with naloxone during antecedent exercise prevents the development of acute EAAF by improving the catecholamine responses and by restoring endogenous glucose production.