J. D. Blackman

Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep.

To define the roles of circadian rhythmicity (intrinsic effects of time of day independent of the sleep or wake condition) and sleep (intrinsic effects of the sleep condition, irrespective of the time of day) on the 24-h variation in glucose tolerance, eight normal men were studied during constant glucose infusion for a total of 53 h. The period of study included 8 h of nocturnal sleep, 28 h of continuous wakefulness, and 8 h of daytime sleep. Blood samples for the measurement of glucose, insulin, C-peptide, cortisol, and growth hormone were collected at 20-min intervals throughout the entire study. Insulin secretion rates were derived from C-peptide levels by deconvolution. Sleep was polygraphically monitored. During nocturnal sleep, levels of glucose and insulin secretion increased by 31 +/- 5% and 60 +/- 11%, respectively, and returned to baseline in the morning. During sleep deprivation, glucose levels and insulin secretion rose again to reach a maximum at a time corresponding to the beginning of the habitual sleep period. The magnitude of the rise above morning levels averaged 17 +/- 5% for glucose and 49 +/- 8% for calculated insulin secretion. Serum insulin levels did not parallel the circadian variation in insulin secretion, indicating the existence of an approximate 40% increase in insulin clearance during the night. Daytime sleep was associated with a 16 +/- 3% rise in glucose levels, a 55 +/- 7% rise in insulin secretion, and a 39 +/- 5% rise in serum insulin. The diurnal variation in insulin secretion was inversely related to the cortisol rhythm, with a significant correlation of the magnitudes of their morning to evening excursions. Sleep-associated rises in glucose correlated with the amount of concomitant growth hormone secreted. These studies demonstrate previously underappreciated effects of circadian rhythmicity and sleep on glucose levels, insulin secretion, and insulin clearance, and suggest that these effects could be partially mediated by cortisol and growth hormone.

Hypoglycemic thresholds for cognitive dysfunction in humans.

Nineteen healthy adult volunteers were studied to define the nature of and threshold for the cognitive dysfunction that occurs during insulin-induced hypoglycemia. The P300 cerebral event-related potential is an electrophysiological correlate of cognitive decision-making processes that can be measured in response to either an auditory or visual stimulus. P300 and reaction time (RT) were recorded from a visual stimulus under euglycemic conditions and at plasma glucose concentrations of 3.3 and 2.6 mM during insulin infusion in 10 subjects. Reducing plasma glucose levels to 3.3 mM was not associated with an increase in either the latency or amplitude of the P300 component or a change in RT. However, further lowering of plasma glucose to 2.6 mM resulted in an increase in the latency of P300 and a prolongation in RT. Similar changes were seen for the auditory P300 in experiments performed on 9 additional subjects in which both auditory and visual stimuli were presented. The prolongation of P300 did not correct immediately when plasma glucose was raised to basal levels with intravenous glucose but returned to normal 45–75 min later, after ingestion of a carbohydrate-containing meal. Analysis of another event-related potential, P140 (a measure of the sensory processes), showed no change in response to hypoglycemia. Prolongation of RT paralleled the prolongation of P300 latency, suggesting that motor processes were not altered. Therefore, hypoglycemia appears to induce abnormalities in decision-making processes. This study shows that 1) insulin-induced hypoglycemia results in cognitive dysfunction when plasma glucose is between 3.3 and 2.6 mM on average, 2)decision-making processes rather than sensory or motor processes appear to be predominantly affected, 3)both auditory or visual P300 and RT were affected, 4) recovery of the cortical dysfunction may lag behind the return of plasma glucose to normal by 45–75 min, and 5) individual sensitivity to the adverse effects of hypoglycemia on cortical function appears to exist, but the physiological basis of this finding is not known.

Hypoglycemic Thresholds for Cognitive Dysfunction in IDDM

Fourteen poorly controlled insulin-dependent diabetes mellitus (IDDM) patients (HbA1c 11 ± 0.5%) with a mean ± SE duration of disease of 15 ± 2 yr were studied to evaluate the hypoglycemic threshold for cognitive dysfunction under insulin-induced hypoglycemia. The P300 event-related potential, a measure of cognitive function, and reaction time (RT) in response to visual stimuli under euglycemic conditions and at plasma glucose concentrations of 3.5 and 2.5 mM (63 and 45 mg/dl, respectively) during a constant insulin infusion were recorded. Baseline P300 latency was similar to that of a nondiabetic control group, but baseline RT was greater in the IDDM group. There was no increase in P300 latency or RT under euglycemic clamp conditions or at a plasma glucose level of 3.5 mM (63 mg/dl). However, when plasma glucose was lowered to 2.5 mM (45 mg/dl), there was an increase in P300 latency and a prolongation of RT. As plasma glucose returned to baseline, P300 latency and RT remained prolonged. After administration of intravenous glucose and a meal, P300 latency and RT returned to baseline. P140, an event-related potential reflecting sensory processes, was not altered. Because P300 latency changes paralleled RT changes, hypoglycemia appears to slow decision-making processes in IDDM. This study revealed that 1) baseline P300 latency is not elevated in poorly controlled IDDM patients, suggesting no cumulative cognitive dysfunction; 2) the hypoglycemic thresholds for cognitive dysfunction in poorly controlled IDDM are between 2.5 and 3.5 mM (45 and 63 mg/dl, respectively)and are similar to those found in control subjects, suggesting no maladaptive CNS response to hypoglycemia; 3) recovery of cerebral dysfunction, as judged by alterations in P300 latency and RT, lagsbehind the disappearance of hypoglycemia; and 4) there is individual variability to the adverse effects of hypoglycemia on cerebral function.

Abnormalities in the ultradian oscillations of insulin secretion and glucose levels in Type 2 (non-insulin-dependent) diabetic patients

SummaryTo investigate the temporal organization of insulin secretion and glucose concentration during fasting in Type 2 (non-insulin-dependent) diabetes mellitus, we studied seven patients with Type 2 diabetes, eight obese non-diabetic control subjects and eight normal weight non-diabetic subjects. Blood sampling for glucose, insulin and C-peptide was performed at 15-min intervals during a 24-h period of fasting for the diabetic and the obese control subjects and during an 8-h fasting period for the normal subjects. Insulin secretion rates were calculated from the peripheral C-peptide concentration profiles. Ultradian oscillations of glucose levels and insulin secretion rates were evident during fasting in all subjects. An additional study with blood sampling at 2-min intervals for 8 h further indicated that this ultradian periodicity is expressed independently of rapid 10–15 min insulin oscillations. There were no differences between diabetic and nondiabetic subjects in the frequency of the ultradian oscillations of insulin secretion (which averaged 12–15 oscillations per 24 h) and in the rate of concomitancy of oscillations of insulin secretion with oscillations in glucose levels, which averaged 63–65%. The relative amplitudes of both the insulin and glucose oscillations were also similar in diabetic and nondiabetic subjects. The major abnormality in patients with Type 2 diabetes was evidenced by spectral analysis, and confirmed by calculations of the distributions of inter-pulse intervals. It consisted of a slowing of the glucose oscillations, without a similar slowing of the oscillations in insulin secretion. This slowing of the glucose oscillations in fasting Type 2 diabetic patients is consistent with our previous observations of sluggish and irregular glucose oscillations in diabetic subjects receiving mixed meals. This partial dissociation between the oscillatory patterns of insulin secretion and glucose levels could represent a sensitive quantitative marker of the breakdown of the insulin-glucose feedback loop in diabetes.

Insulin Secretory Profiles and C-Peptide Clearance Kinetics at 6 Months and 2 Years After Kidney-Pancreas Transplantation

Glucose, insulin secretion, and insulin secretory pulses were measured by deconvolution of peripheral C-peptide concentrations in 10 IDDM recipients of a combined kidney-pancreas allograft 6 mo post-transplantation and were compared with 10 matched nondiabetic control subjects. Seven of the 10 recipients were restudied 2 yr post-transplantation. To control for immunosuppressive therapy, 6 patients with a kidney allograft also were studied. Pancreatic insulin secretion rates were evaluated over a 24-h period with three mixed meals. Six months post-transplantation, fasting (5.3 ± 0.1 vs. 5.3 ± 0.1 mM), average 24-h (6.0 ± 0.1 vs. 5.7 ± 0.1 mM), and meal-related (6.1 ± 0.3 vs. 5.8 ± 0.2 mM) plasma glucose levels were not different in control subjects and recipients, respectively. Total 24-h insulin secretion rates were similar between the two groups (150 ± 15 vs. 182 ± 24 nmol · m−2 · 24 h−1). However, post-transplantation, the relationship between basal and meal-stimulated insulin secretion was altered with increased basal insulin secretion (52.2 ± 6.4 vs. 97.4 ± 12.5 pmol · m−2 · min−1 P < 0.004) and reduced meal-related secretion. The proportion of total 24-h insulin secretion comprised by basal secretion was 44 ± 4% in the control subjects vs. 73 ± 5% in recipients. The number of ultradian oscillations of insulin secretion identified in each 24-h period by pulse analysis was similar in control subjects and recipients (11.9 ± 0.9 vs. 10.4 ± 0.5 oscillations/24 h). Two years post-transplantation, the glucose profiles and oscillatory insulin secretory patterns remained intact. Basal insulin secretion was 76 ± 11 pmol · m−2 · min−1 and 24-h insulin secretion was 167 ± nmol m−2 24 h−1. Six kidney-transplant recipients studied showed that 47 ± 3% of 24-h insulin secretion was basal secretion. This finding supported the idea that altered meal secretory patterns observed in the kidney-pancreas recipients were not the result of immunosuppressive therapy. After combined kidney-pancreas transplantation 1) plasma glucose profiles remain normal 2 yr post-transplantation, 2) clearance of C-peptide is reduced, 3) basal insulin secretion is increased but meal responses are reduced, and 4) the normal oscillatory pattern of insulin secretion persists.

Clinical Evaluation of a Semipermeable Polymeric Membrane Dressing for the Treatment of Chronic Diabetic Foot Ulcers

OBJECTIVE To evaluate the utility of a semipermeable polymeric membrane dressing for the treatment of chronic diabetic foot ulcers. RESEARCH DESIGN AND METHODS Nineteen subjects with either insulin- dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM) and foot ulcers were randomly assigned to the polymeric dressing or conventional wet-to-dry saline dressings. Subjects had foot ulcer site measurements performed every 3 weeks. The subjects using conventional therapy were allowed to cross over to polymeric dressing after 2 months. RESULTS At the end of 2 months, in the patients using the polymeric dressing, ulcer size was reduced to 35 ± 16% of baseline. The patients on conventional therapy had an ulcer size of 105 ± 28% of baseline (P < 0.03, polymeric vs. conventional). Patients initially treated with wet-to-dry saline were crossed over into the polymeric membrane treatment and demonstrated a decrease to 35 ± 11% of baseline size (P < 0.02) after an additional 2 months. CONCLUSIONS The semipermeable polymeric membrane dressing is a useful therapeutic option for treating uncomplicated chronic diabetic foot ulcers.

Prior feeding Alters the Response to the 50-g Glucose Challenge Test in Pregnancy: The Staub-Traugott Effect revisited

OBJECTIVE To examine the effect of prior meal ingestion on the glucose, insulin, and C-peptide response to a 50-g glucose challenge test in the third trimester of pregnancy. RESEARCH DESIGN AND METHODS Ten pregnant women with gestational diabetes mellitus and 12 nondiabetic pregnant control subjects matched for age and weight underwent a 50-g glucose challenge test on three occasions within a 2-wk period, in random order. On one occasion the test was administered in the fasting state (fasting glucose challenge test), on a second occasion the test was administered 1 h after ingestion of a standard mixed meal (1-h postprandial study), and on a third occasion the test was administered 2 h after ingestion of a standard mixed meal (2-h postprandial study). RESULTS In the control subjects, the plasma glucose level 1 h after ingestion of 50 g of glucose was higher in the fasting study (7.8 ±0.4 mM, 7 of 12 subjects with glucose ≥7.8 mM) than in the 1-h postprandial study (6.7 ± 0.3 mM, 3 of 12 subjects with glucose ≥7.8 mM) and the 2-h postprandial study (6.3 ± 0.4 mM, 3 of 12 with glucose ≥7.8 mM) (P < 0.01). In the postprandial studies of control subjects, insulin and C-peptide levels were higher at the time of ingestion of the 50 g of glucose, but the early (1 h) insulin secretory response was less than in the fasting study. In the diabetic patients, glucose levels 1 h after 50-g glucose ingestion were similar in the fasting study (10.5 ± 0.4 mM, no subjects with glucose value <7.8 mM) and the 1-h postprandial study (11.0 ± 0.6 mM, 1 subject with glucose <7.8 mM), but was lower in the 2-h postprandial study (9.3 ± 0.3 mM, 1 subject with glucose <7.8 mM) (P < 0.03). In contrast to the control subjects, the insulin secretory response to 50 g of oral glucose was greater in the two postprandial studies than in the fasting study. CONCLUSIONS We have reached the following conclusions. 1) In nondiabetic gravidas, plasma glucose concentrations 1 h after ingestion of a 50-g oral glucose load are higher if administered in the fasting state compared with the postprandial state. 2) During normal pregnancy the Staub-Traugott Effect, i.e., improved glucose disposal after successive glucose load administrations, occurs and appears to be caused by mechanisms other than enhanced insulin secretion with successive glucose loads. 3) The effect of the prandial state on plasma glucose response to the 50-g glucose challenge test used to screen for gestational diabetes mellitus may be of sufficient magnitude to significantly alter the operating characteristics, i.e., sensitivity and specificity, of this test.

Oscillatory Insulin Secretion After Pancreas Transplant

In vivo studies of β-cell secretory function have demonstrated the existence of rapid insulin oscillations of small amplitude recurring every 8–15 min in normal subjects. This study evaluated the effects of pancreas transplant on rapid insulin oscillations. Samples for glucose, insulin, and C-peptide were drawn during constant glucose infusion at 2-min intervals for 90 min from six successful Px patients with type I diabetes mellitus, from six normal nondiabetic control subjects, and from three Kx subjects. A computerized algorithm (ULTRA) was used for pulse detection. In the Px group, the average insulin pulse period was significantly shorter than in both the control and Kx groups (Px 8.1 ± 0.5, control 12.5 ± 0.7, Kx 12.4 ± 0.5 min, P < 0.0005). By contrast, the C-peptide pulse periods (Px 16.8 ± 2.3, control 14.7 ± 1.2, Kx 15.3 ± 1.5 min) were similar in the three groups. Spectral analysis confirmed that the frequency of the insulin pulses was increased in the Px group. The absolute amplitude of the insulin pulses was greater in the Px group (P < 0.001) while the amplitude of the C-peptide pulses did not differ between the groups. Cross-correlation analysis demonstrated maximal correlation coefficients at a lag of 0 min between insulin and C-peptide (control r = 0.33, P < 0.0001; Kx r = 0.17, P = 0.06) and between insulin and glucose (control r = 0.21, P < 0.001; Kx r = 0.20, P < 0.02) in the control and Kx groups, respectively, whereas no significant correlations were observed at any lag in the Px group. Thus, insulin oscillations, which are of larger amplitude and occur with greater frequency than in normal control subjects, may be detected in the peripheral circulation after pancreas transplant. Although their persistence after transplant supports the hypothesis that they reflect the existence of an intrinsic islet cell pacemaker, the increased frequency of the oscillations in the Px group raises the possibility that this intrinsic pacemaker in normal subjects may be modified by extrinsic neural factors.

Postprandial triglyceride response in Type 1 (insulin-dependent) diabetes mellitus is not altered by short-term deterioration in glycaemic control or level of postprandial insulin replacement

SummaryThe effect of deteriorating glycaemic control on the lipoprotein responses to the ingestion of a high fat meal was investigated in seven normolipidaemic Type 1 (insulindependent) diabetic patients and the results were compared with corresponding responses in seven normolipidaemic control subjects. In addition, the importance of insulin in regulating the postprandial lipoprotein responses was examined by comparing the results obtained from the diabetic patients maintained on a basal infusion of insulin throughout the study with those obtained when a step-up, step-down insulin infusion was administered following the meal. Vitamin A was added to the test meal in all subjects to trace the metabolism of the chylomicron (Sf> 1000) and non-chylomicron (Sf< 1000) fractions in the postprandial period. No differences in fasting and postprandial triglyceride levels nor in the concentration of the chylomicron and non-chylomicron fractions were observed between diabetic and control subjects. In the diabetic patients short-term (two-week) deterioration in glycaemic control did not have any adverse influence on the basal and postprandial lipid responses. However, while the amount of insulin administered after the meal in the diabetic patients did not have any effect on the postprandial triglyceride or chylomicron responses, the concentration of non-esterified fatty acids was significantly higher (p< 0.0005) when only a basal infusion of insulin was administered. In conclusion: 1) Short-term deterioration in glycaemic control does not adversely affect lipoprotein concentrations in Type 1 diabetes. 2) Non-esterified fatty acids appear to be a more sensitive index of insulinization postprandially than triglycerides.

Lack of effect of high-dose biosynthetic human C-peptide on pancreatic hormone release in normal subjects

We studied the effect of high doses of biosynthetic human C-peptide on pancreatic hormone secretion in response to oral (75 g) and intravenous [( IV] 0.33 g/kg of D50%) glucose on normal volunteers. The infusion of human C-peptide at a rate of 360 ng/kg/min body weight, increased the plasma C-peptide concentration from a basal level of 0.32 +/- 0.04 pmol/mL to 38.5 +/- 1.8 pmol/ml. Overall, C-peptide had no significant effect on the serum levels of glucose, insulin, proinsulin, glucagon, and pancreatic polypeptide, either under basal conditions or following IV and oral glucose administration. However, small decreases in glucose and insulin concentrations that were not statistically significant were seen during the first hour after C-peptide infusion. The results of the present studies are therefore consistent with the conclusion that even supraphysiologic plasma concentrations of infused C-peptide do not affect basal insulin secretion or overall insulin secretory responses to oral or IV glucose. However, we cannot definitively exclude a small reduction in insulin secretion in the first hour after oral glucose ingestion.