Euglycemic progression: worsening of diabetic retinopathy in poorly controlled type 2 diabetes in minorities.

AIMS: In type 2 diabetes, early effects of strict near-normalization of glucose control on macrovascular and microvascular disease are still uncertain. We evaluated the effects of early dramatic improvement in glycemia on retinal disease in poorly controlled diabetes. METHODS: A retrospective, case-control study in public hospital patients with type 2 diabetes, who had annual retinal imaging as part of a case management program or standard diabetes care. Patients included had ≥2 two retinal images ≥1 one year apart, and at least 3 HbA1C measurements. Retinal images were graded using a modified Scottish Diabetic Retinopathy grading scheme. An 'intensive' group (n=34) with HbA1C decrease >1.5% was compared with randomly chosen patients (n=34) with minimal HbA1C changes. RESULTS: Mean HbA1C (±SEM) over two years was similar in intensive (8.5 ± 0.21%) and control groups (8.1 ± 0.28%, p=NS). However, the intensive group had higher baseline HbA1C and a mean maximal decrease of 4.0 ± 0.41% in contrast to the control group (0.2 ± 0.11%). Retinopathy grade progressed +0.7 ± 0.25 units from baseline in the intensive group (p=0.015), a 22.6% worsening. The control group changed minimally from baseline (0.03 ± 0.14 units, p=NS). Change in retinopathy grade was significantly different between groups (p=0.02). More eyes worsened by ≥ 1 retinal grade (p=0.0025) and developed sight-threatening retinopathy (p=0.003) in the intensive group. Visual acuity was unchanged. CONCLUSIONS: Diabetic retinopathy significantly worsened in poorly controlled type 2 diabetes after early intensification of glycemic control and dramatic HbA1C change. Retinal status should be part of risk-factor evaluation in patients likely to experience marked reductions in HbA1C in poorly controlled diabetes.

Counterregulatory hormones oscillate during steady-state hypoglycemia.

During hypoglycemia, the magnitude of the counterregulatory response depends on the extent of plasma glucose reduction. However, our clinical observations during steady-state hypoglycemia indicate that symptom severity can change independently of plasma glucose concentrations, i.e., symptoms appeared to fluctuate despite stable glucose levels. This study was therefore designed to test the hypothesis that hormonal and symptomatic responses to hypoglycemia are pulsatile. Seven healthy subjects had serial blood sampling at 3-min intervals during 90 min of insulin-induced hypoglycemia. Mean +/- SE plasma glucose levels plateaued at 62 +/- 3 mg/dl. Counterregulatory hormones were significantly elevated (P < 0.05-0. 01, except norepinephrine) and strikingly pulsatile. Cluster analysis revealed pulses of large magnitude in plasma glucagon, epinephrine, and norepinephrine concentrations. Amplitudes were, respectively, 72 +/- 4, 64 +/- 8, and 48 +/- 3% of the mean. Interpeak intervals were 27 +/- 7, 19 +/- 4, and 25 +/- 5 min, respectively. Symptom score and cardiovascular responses were also pulsatile; their peaks were found to coincide with epinephrine peaks. We conclude that hormonal and symptomatic counterregulation in hypoglycemia, while critically driven by plasma glucose levels, is also influenced by an endogenous pulsatility that exists despite steady-state glucose concentrations.

Erratic oscillatory characteristics of plasma insulin concentrations in patients with insulinoma: mechanism for unpredictable hypoglycemia.

Patients with insulin-producing tumors may have hypoglycemic symptoms at unpredictable times. This study evaluated whether plasma insulin oscillations, known to occur in normal individuals but not explored in patients with insulinomas, could be an underlying mechanism for such events. Nine normal subjects and five patients with proven insulinomas were studied in the fasting state. Serial sampling of arterialized blood over 80-100 min, at 2- or 3-min intervals was performed. In normal subjects, mean plasma glucose and insulin concentrations were 5.3 +/- 0.1 mmol/L and 58 +/- 9 pmol/L, respectively. Regular, low-amplitude plasma insulin oscillations were observed, with a period of 10-17 min. The subjects with insulinomas had lower mean plasma glucose and higher insulin concentrations than controls, 3.6 +/- 0.3 mmol/L (P = 0.01) and 150 +/- 42 pmol/L (P = 0.01), respectively. They also had insulin oscillations that appeared unstable as a result of variability in duration and amplitude compared with controls. The insulin pulses were irregular, and interpeak intervals varied between 4-54 min in different subjects; in some subjects, the amplitude was also variable, with sudden spontaneous pulses as high as 565 pmol/L, with an associated glucose decrement. We conclude that large spontaneous bursts of insulin secretion occur in patients with insulinomas as part of an erratic pattern of oscillatory insulin secretion, and these can account for unpredictable occurrences of hypoglycemia.

Accuracy of plasma glucose measurements in the hypoglycemic range.

OBJECTIVE: This study was designed to evaluate three different enzymatic methods for glucose measurement in plasma samples with special emphasis on glucose concentrations in the hypoglycemic range. RESEARCH DESIGN AND METHODS: Glucose dehydrogenase (Hemo-Cue analyzer), glucose oxidase (YSI analyzer), and hexokinase (Abbott analyzer) methods were used to measure plasma samples that were obtained during research studies. RESULTS: Mean glucose concentrations (n = 240) were 5.3 +/- 0.2, 5.4 +/- 0.2, and 5.6 +/- 0.2 mM (95.6 +/- 3.9, 96.7 +/- 3.9, and 101.6 +/- 4.0 mg/dl) using glucose dehydrogenase, glucose oxidase, and hexokinase, respectively (NS). In the hypoglycemic range, mean glucose concentrations with each method retained the same hierarchy of measurements: 2.7 +/- 0.05, 2.8 +/- 0.04, and 2.9 +/- 0.03 mM (48.4 +/- 0.9, 50.6 +/- 0.8, and 52.3 +/- 0.6 mg/dl) by glucose dehydrogenase, glucose oxidase, and hexokinase, respectively (P < 0.005). Individual glucose dehydrogenase measurements (n = 240) correlated well with glucose oxidase and hexokinase, r = 0.99, and were considerably easier to perform at the bedside. The differences between the glucose measurement methods were consistent and similar in low, normal, and high concentration ranges. CONCLUSIONS: We conclude that any interpretation or comparison of critical clinical and research measurements of glucose in different settings take into account methodological differences, particularly in the hypoglycemic range.

Plasma glucose thresholds for counterregulation after an oral glucose load.

Glucose counterregulation (GCR) plays an important role in the transition between exogenous and endogenous glucose delivery after an oral glucose load. This response is initiated when plasma glucose concentrations are decreased below threshold levels, previously defined in studies of insulin-induced hypoglycemia. In this study, we tested the plasma glucose thresholds for activation of the GCR response under more physiologic circumstances, ie, after glucose ingestion. We studied 20 normal subjects for 300 minutes after 75 g of oral glucose. Between 150 and 300 minutes, blood samples and symptom scores were obtained at 10-minute intervals. After oral glucose, individual glucose nadirs were observed over a wide time range (160 to 290 minutes). Mean glucose concentrations decreased from 5.3 +/- 0.2 mmol/L at 30 minutes before the nadir (-30 minutes) to 3.8 +/- 0.2 mmol/L at the nadir (0 minutes). Mean plasma epinephrine concentrations increased from 210 +/- 35 pmol/L, were significantly elevated at -10 minutes (P < .05), and peaked at +20 minutes (1,008 +/- 184 pmol/L, P < .001). Mean plasma glucagon concentrations were significantly increased over baseline (100%) at +10 minutes (P < .001) and peaked at +30 minutes (122% +/- 7%, P < .001). Seven subjects (out of 15 tested) developed symptoms. Quantitative evaluation revealed a peak in the mean symptom score at +20 minutes, an increase from 0.4 +/- 0.3 to 2.6 +/- 0.1 arbitrary units (P < .06).(ABSTRACT TRUNCATED AT 250 WORDS)