Plasma Glucose Fluctuations Research Articles

Reasons for Early Ocular Hypertension after Uneventful Cataract Surgery

To discuss the reasons for and measurements of early ocular hypertension after uneventful phacoemulsification and intraocular lens (IOL) implantation. This was a retrospective review of patients who had early ocular hypertension after cataract surgery from a single-surgeon practice that medications failed to control or required additional surgery from September 2011 to January 2013. Of the 1270 eyes that had cataract surgery by one surgeon in our department in 16 months, 12 (9.4‰) eyes of 12 patients met the inclusion criteria. The mean postoperative intraocular pressure (IOP) peak was 41 (range 32-62) mm Hg. The median time of initial onset after cataract surgery was 3.5 days (range 1-60 days). Six eyes had antiglaucoma surgery history. Ahmed valve implantation with mitomycin C (MMC) was applied to 4 eyes. Two eyes underwent 5-fluorouracil needling revision with MMC. The IOP dropped in 3 eyes only in the case that the conventional topical corticosteroid agent was stopped, diagnosed as steroid responders. One eye of a patient with diabetes mellitus (DM) developed pseudophakic pupillary block angle-closure glaucoma due to the plasma glucose fluctuations. The IOP was controlled after Nd:YAG laser iridotomies. Residual cortex caused ocular hypertension in 2 eyes and surgical aspirations were performed. Following monitoring of IOP for 6 to 24 months, all eyes were within the normal range. Patients with history of glaucoma surgery; high myopia, especially in young age; and DM merit particular observation and treatment for possible IOP elevation following cataract surgery.

Multiple Functional Ingredient Approach in Formulating Dietary Supplement for Management of Diabetes: A Review

Food and nutrition science has moved from identifying and correcting nutritional deficiencies to designing foods that promote optimal health and reduce the risk of disease. Diabetes is rapidly emerging as a pandemic. It is also accompanied by several health implications viz. cardiovascular diseases, obesity, hypertension, cancer, depression, and eating disorders. International Diabetes Federation estimates that in 2010, India is home to 50.8 million diabetics and the number is expected to go up to a whopping 87 million by 2030. The primary goal of medical nutrition therapy was to design special dietary products for patients with hyperglycemia, intended in controlling postprandial plasma glucose fluctuations and hypercholesterolemic tendencies. However, an effective way to minimize these health risks could be through modifications in the diet by inclusion of multiple functional ingredients, aimed for their concerted role in management of individuals suffering with diabetes.

Hypoglycaemia during pregnancy in women with Type 1 diabetes

To explore incidence, risk factors, possible pathophysiological factors and clinical management of hypoglycaemia during pregnancy in women with Type 1 diabetes. Literature review. In women with Type 1 diabetes, severe hypoglycaemia occurs three to five times more frequently in early pregnancy than in the period prior to pregnancy, whereas in the third trimester the incidence of severe hypoglycaemia is lower than in the year preceding pregnancy. The frequency distribution of severe hypoglycaemia is much skewed, as 10% of the pregnant women account for 60% of all recorded events. Risk factors for severe hypoglycaemia during pregnancy include a history with severe hypoglycaemia in the year preceding pregnancy, impaired hypoglycaemia awareness, long duration of diabetes, low HbA(1c) in early pregnancy, fluctuating plasma glucose values (≤ 3.9 mmol/l or ≥ 10.0 mmol/l) and excessive use of supplementary insulin injections between meals. Pregnancy-induced nausea and vomiting seem not to be contributing factors. Striving for near-normoglycaemia with focus on reduction of plasma glucose fluctuations during pregnancy should have high priority among clinicians with the persistent aim of improving pregnancy outcome among women with Type 1 diabetes. Pre-conception counselling, carbohydrate counting, use of insulin analogues, continuous subcutaneous insulin infusion (insulin pump) therapy and real-time continuous glucose monitoring with alarms for low glucose values might be relevant tools to obtain near-normoglycaemia without episodes of severe hypoglycaemia.

Human metabolic adaptations and prolonged expensive neurodevelopment: A review

Abstract1. After weaning, human hunter-gatherer juveniles receive substantial (≈3.5-7 MJ day^-1^), extended (≈15 years) and reliable (kin and nonkin food pooling) energy provision.2. The childhood (pediatric) and the adult human brain takes a very high share of both basal metabolic rate (BMR) (child: 50-70%; adult: ≈20%) and total energy expenditure (TEE) (child: 30-50%; adult: ≈10%).3. The pediatric brain for an extended period (≈4-9 years-of-age) consumes roughly 50% more energy than the adult one, and after this, continues during adolescence, at a high but declining rate. Within the brain, childhood cerebral gray matter has an even higher 1.9 to 2.2-fold increased energy consumption. 4. This metabolic expensiveness is due to (i) the high cost of synapse activation (74% of brain energy expenditure in humans), combined with (ii), a prolonged period of exuberance in synapse numbers (up to double the number present in adults). Cognitive development during this period associates with volumetric changes in gray matter (expansion and contraction due to metabolic related size alterations in glial cells and capillary vascularization), and in white matter (expansion due to myelination). 5. Amongst mammals, anatomically modern humans show an unique pattern in which very slow musculoskeletal body growth is followed by a marked adolescent size/stature spurt. This pattern of growth contrasts with nonhuman primates that have a sustained fast juvenile growth with only a minor period of puberty acceleration. The existence of slow childhood growth in humans has been shown to date back to 160,000 BP. 6. Human children physiologically have a limited capacity to protect the brain from plasma glucose fluctuations and other metabolic disruptions. These can arise in adults, during prolonged strenuous exercise when skeletal muscle depletes plasma glucose, and produces other metabolic disruptions upon the brain (hypoxia, hyperthermia, dehydration and hyperammonemia). These are proportional to muscle mass.7. Children show specific adaptations to minimize such metabolic disturbances. (i) Due to slow body growth and resulting small body size, they have limited skeletal muscle mass. (ii) They show other adaptations such as an exercise specific preference for free fatty acid metabolism. (iii) While children are generally more active than adolescents and adults, they avoid physically prolonged intense exertion. 8. Childhood has a close relationship to high levels of energy provision and metabolic adaptations that support prolonged synaptic neurodevelopment.

Human metabolic adaptations and prolonged expensive neurodevelopment: A review

Abstract1. After weaning, human hunter-gatherer juveniles receive substantial (≈3.5-7 MJ day^-1^), extended (≈15 years) and reliable (kin and nonkin food pooling) energy provision.2. The childhood (pediatric) and the adult human brain takes a very high share of both basal metabolic rate (BMR) (child: 50-70%; adult: ≈20%) and total energy expenditure (TEE) (child: 30-50%; adult: ≈10%).3. The pediatric brain for an extended period (≈4-9 years-of-age) consumes roughly 50% more energy than the adult one, and after this, continues during adolescence, at a high but declining rate. Within the brain, childhood cerebral gray matter has an even higher 1.9 to 2.2-fold increased energy consumption. 4. This metabolic expensiveness is due to (i) the high cost of synapse activation (74% of brain energy expenditure in humans), combined with (ii), a prolonged period of exuberance in synapse numbers (up to double the number present in adults). Cognitive development during this period associates with volumetric changes in gray matter (expansion and contraction due to metabolic related size alterations in glial cells and capillary vascularization), and in white matter (expansion due to myelination). 5. Amongst mammals, anatomically modern humans show an unique pattern in which very slow musculoskeletal body growth is followed by a marked adolescent size/stature spurt. This pattern of growth contrasts with nonhuman primates that have a sustained fast juvenile growth with only a minor period of puberty acceleration. The existence of slow childhood growth in humans has been shown to date back to 160,000 BP. 6. Human children physiologically have a limited capacity to protect the brain from plasma glucose fluctuations and other metabolic disruptions. These can arise in adults, during prolonged strenuous exercise when skeletal muscle depletes plasma glucose, and produces other metabolic disruptions upon the brain (hypoxia, hyperthermia, dehydration and hyperammonemia). These are proportional to muscle mass.7. Children show specific adaptations to minimize such metabolic disturbances. (i) Due to slow body growth and resulting small body size, they have limited skeletal muscle mass. (ii) They show other adaptations such as an exercise specific preference for free fatty acid metabolism. (iii) While children are generally more active than adolescents and adults, they avoid physically prolonged intense exertion. 8. Childhood has a close relationship to high levels of energy provision and metabolic adaptations that support prolonged synaptic neurodevelopment.

Glycemic index and colorectal carcinogenesis.

Misciagna et al. [1] report the results of an interesting study of fasting serum fructosamine, glucose, insulin, and triglycerides in relation to risk of colorectal adenoma in this issue of the journal. The results are suggestive of an elevated adenoma risk with higher fructosamine and triglyceride levels and with lower fasting insulin level. The authors address some potential methodologic limitations, including selection, measurement bias and confounding. Thus, these issues will not be dealt with in this commentary. Instead, this will focus instead on the contributions of this study to our understanding of colorectal carcinogenesis. The insulin resistance or metabolic syndrome is characterized by a number of abnormalities, including dyslipidemia (low concentrations of HDL cholesterol, and elevated concentrations of triglycerides, VLDL, and small dense LDL), hypertension, chronic inflammation, procoagulation, and impaired fibrinolysis [2]. Obesity, in particular visceral adiposity, physical inactivity and a Western dietary pattern are involved in the etiology of this syndrome. The similarity of risk factors for colon cancer and for factors related to the insulin resistance syndrome was first described in detail about a decade ago [3, 4]. Since that time, an impressive body of epidemiologic data has accumulated indicating that colon cancer risk is associated with the insulin resistance syndrome. This evidence is strong from studies based on determinants of the insulin resistance syndrome (obesity, abdominal distribution of adiposity, physical inactivity), and on the major disease consequence of this syndrome, type 2 diabetes [5]. Studies of hypertriglyceridemia, hyperglycemia, and hyperinsulinemia in relation to colon cancer risk are suggestive, but not definitive at this point. For colorectal or colon cancer [6-10], and for adenoma [11, 12], a number of studies have shown a significant or borderline significant increased risk associated with hyperglycemia. Higher level of glycosylated hemoglobin (HbA1e), a marker of average glycemia over the previous 2 months, was associated with an elevated risk of colorectal cancer in one cohort study [13], but not in a smaller cohort study [14]. A novel feature of the study by Misciagna et al. is the use of fructosamine, which is an indicator of total glycated proteins in the serum, and which correlates with average blood glucose over a period of several weeks. Although HbAI is generally considered as the gold standard for measurement of glycemic control in diabetic patients, the authors suggest some potential theoretical advantages of fructosamine over HbAlc in the context of studying colorectal carcinogenesis. They cite evidence that fructosamine is glycated more rapidly than hemoglobin [15], and thus might better indicate a peak in blood glucose following a meal with high glycemic load. They also cite a study that fou d that in non-diabetics, 6 weeks of a high glycemic diet increased levels of fructosamine but not of HbA1c [16]. In addition, in a recent meta-analysis of randomized studies of low-glycemic index diets in the management of diabetes, results were stronger for a reduction of fructosamine than of HbA1~ if the duration of the study was less than 6 weeks [17]. HbA1~ measures non-enzymatic glycosylation of hemoglobin in erythrocytes, whereas fructosamine measures non-enzymatic glycation of proteins in the same compartment of plasma glucose; thus, fructosamine might better reflect plasma glucose fluctuations. A recent study indicated that the discordance between HbAjc and fructosamine in an individual is stable over time, and may possibly have some pathophysiologic relevance and not merely reflect differences in turnover of the affected proteins [18]. Clearly more study is required to better understand what physiologic aspects HbAIc and fructosamine are measuring, how they differ, and how they relate to colorectal carcinogenesis. Although HbAI is considered the gold standard for assessing glycemic control for diabetics, HbA1c may not necessarily be the superior measure of postprandial spikes from a high glycemic diet in non-diabetics, which could possibly be most relevant for the study of colorectal cancer. Because many studies of HbAIc and fructosamine have been done in diabetics, it is critical to get more information in non-diabetics. The findings from the study by Misciagni et al., while requiring confirmation, suggest that an indicator of level of glucose in the blood sensitive to foods with a high glycemic index influences colorectal carcinogenesis. A recent prospective study found that diets with a high glycemic index and load were associated with an increased risk of colon cancer [19]. However, not all studies are supportive [20]. If insulinemic rather than glycemic spikes are most etiologically relevant, the inconsistent findings for dietary glycemic index would not be surprising because the glycemia response explains only about 23% of the variability in insulinemia [21]. Besides glycemic index,

Sleepiness, performance, and neuroendocrine function during sleep deprivation: effects of exposure to bright light or exercise.

The temporal profiles of subjective fatigue (as assessed by the Stanford Sleepiness Scale), of cognitive performance (on a digit symbol substitution test and a symbol copying task), of body temperature, and of the peripheral concentrations of melatonin, thyroid-stimulating hormone (TSH), and cortisol were obtained simultaneously at frequent intervals in 17 normal young subjects submitted to a 43-h period of constant routine conditions involving continuous wakefulness at bed rest in dim indoor light. The subjects had knowledge of time of day. Caloric intake was exclusively in the form of an intravenous glucose infusion, and plasma glucose levels were monitored continuously in 8 of the 17 subjects. Under these conditions, fluctuations in plasma glucose reflect primarily changes in glucose use because endogenous glucose production is suppressed by the exogenous infusion. Following the completion of a baseline constant routine study, the volunteers participated in two subsequent studies using the same protocol to determine the immediate psychophysiological effects of exposure to a 3-h pulse of bright light or to a 3-h pulse of physical exercise. Sleepiness and performance varied in a mirror image, with significant negative correlations. Sleepiness scores were minimal around noon and then increased at a modest rate throughout the rest of the normal waking period. Staying awake during usual bedtime hours was associated with an acceleration in the rate of increase in sleepiness, which coincided with decreasing body temperature, rapidly rising cortisol concentrations, and maximal levels of melatonin and TSH. When body temperature reached its nadir, a further major increase in sleepiness occurred in parallel with a pronounced decrease in plasma glucose (reflecting increased glucose use). Recovery from maximal sleepiness started when blood glucose levels stopped falling and when significant decreases in cortisol and melatonin concentrations were initiated. Lower levels of subjective sleepiness resumed when glucose concentrations and body temperature had returned to levels similar to those observed prior to sleep deprivation and when melatonin and TSH concentrations had returned to daytime levels. The synchrony of behavioral, neuroendocrine, and metabolic changes suggests that circulating hormonal levels could exert modulatory influences on sleepiness and that metabolic alterations may underlie the sudden increase in fatigue consistently occurring at the end of a night of sleep deprivation. Effects of bright light or exercise exposure on subjective sleepiness appeared to be critically dependent on the timing of exposure.

Nonenzymic glycation of apolipoprotein B in patients with insulin- and noninsulin-dependent diabetes mellitus

Objective: To evaluate the level of nonenzymatic glycation of apolipoprotein B in patients with insulin and noninsulin dependent diabetes mellitus. Methods: Using a method based on a combination of affinity chromatography and immunonephelometry, we measured the concentration of glycated apolipoprotein B (apo B) in serum of 140 diabetic patients, 43 insulin-dependent (IDDM), and 97 noninsulin-dependent (NIDDM), and 45 nondiabetic control subjects. Results: Although total apo B concentration in serum was significantly increased only in NIDDM patients, both groups of diabetics showed higher percentages of glycated apo B (IDDM, 4.84 ± 0.8%; NIDDM, 5.61 ± 1.1%) than did control subjects (4.28 ± 1.0%), the greatest percentage (5.80%) being found in patients with diabetic nephropathy. No significant correlations were found between glycated apo B and the traditional parameters of glycemic control, such as glycated hemoglobin and fructosamines, and direct influence by sudden plasma glucose fluctuations on apo B glycation was not shown either, perhaps for a low inherent glycability of this apolipoprotein. Conclusions: It is unclear if these low proportions of glycated apo B in vivo may significantly affect lipoprotein metabolism assuming a pathophysiological role in atherogenesis.

Hypothalamic-pituitary-adrenal activation following endotoxin administration in the developing rat: a CRH-mediated effect.

The present studies assessed hypothalamic-pituitary-adrenal (HPA) responses following immune activation with endotoxin (i.p.) in three-day old Long Evans rats. Marked plasma corticosterone (B), adrenocorticotrophic hormone (ACTH) responses and biphasic fluctuations in plasma glucose were maximal at a dose of 0.05 mg/kg. HPA responses peaked between 3-5 h following immune challenge and plasma ACTH and B responses were greater in female than in male rat pups. Plasma levels of corticosterone binding globulin (CBG) were reduced in males and substantially increased in females during the peak HPA response. Changes in plasma glucose were biphasic with slight increases when ACTH and B levels were maximal, but hypoglycemia was evident once plasma B levels returned to resting values. Endotoxin challenge reduced median eminence corticotropin-releasing hormone (CRH) levels at times corresponding with elevated HPA activity, and prior i.c.v. injection of the CRH antagonist, alpha-helical CRH, significantly attenuated elevations in plasma ACTH and B. In addition, alpha-helical CRH pretreatment completely blocked endotoxin-induced changes in plasma CBG in both males and females. These findings support the view that endotoxin-induced HPA activation in the neonate may occur via CRH.

Estimation of plasma glucose fluctuation with a combination test of hemoglobin A 1c and 1,5-anhydroglucitol

We investigated the effect of plasma glucose fluctuation on hemoglobin A 1c (HbA 1c) and plasma 1,5-anhydroglucitol (AG) levels, especially in insulin-dependent diabetes mellitus (IDDM). Plasma AG is a new marker that provides sensitive and analytical information on glycemic control. The basic mechanisms underlying both the reduction and recovery of the plasma AG level, ie, the excretion into urine with glucosuria and the amount supplied to the body, were presumed to be similar in IDDM and non-insulin-dependent diabetes mellitus (NIDDM) patients. The correlation coefficient for mean plasma glucose and AG was −.591, and it was .578 for mean plasma glucose and HbA 1c in IDDM patients. In NIDDM, the correlation between mean plasma glucose and AG was −.869, and between mean plasma glucose and HbA 1c, .875. The plasma AG levels in the IDDM group showed a lower range than in the NIDDM group, even with similar HbA 1c levels. All the cases showing lower plasma AG levels among those with similar HbA 1c levels manifested greater fluctuation of plasma glucose and a larger amount of urinary glucose. The lower AG level in IDDM patients was reversible to the level in NIDDM patients when the greater fluctuation of plasma glucose was corrected. Thus, it was suggested that because urinary glucose excretion is intermittently high in IDDM patients, plasma AG is frequently low, even though the mean plasma glucose and HbA 1c levels suggest good control. The results of the present study indicate the significance of both plasma glucose fluctuation and mean plasma glucose level for an evaluation of glycemic control, especially in IDDM patients, and imply the danger of frequent hypoglycemia if the improvement of glycemic control is evaluated by HbA 1c alone.

Effects of dietary fiber supplementation on glycemic control in dogs with alloxan-induced diabetes mellitus

SUMMARY The effect of a high insoluble-fiber (if) diet containing 15% cellulose in dry matter, high soluble-fiber (sf) diet containing 15% pectin in dry matter, and low-fiber (lf) diet on glycemic control in 6 dogs with alloxan-induced insulin-dependent diabetes mellitus was evaluated. Each diet contained > 50% digestible carbohydrate in dry matter. A crossover study was used with each dog randomly assigned to a predetermined diet sequence. Each dog was fed each diet for 56 days. Caloric intake was adjusted weekly as needed to maintain each dog within 1.5 kg of its body weight measured prior to induction of diabetes mellitus. All dogs were given pork lente insulin and half of their daily caloric intake at 12-hour intervals. Mean (± sem) daily caloric intake was significantly (P < 0.05) less when dogs consumed the if diet vs the sf and lf diets (66 ± 3 kcal/kg, 81 ± 5 kcal/kg, and 79 ± 4 kcal/kg, respectively). Serum alkaline phosphatase activity was significantly (P < 0.05) higher when dogs consumed the lf diet vs the if and sf diets (182 ± 37 IU/L, 131 ± 24 IU/L, and 143 ± 24 IU/L, respectively). Mean postprandial plasma glucose concentration measured every 2 hours for 24 hours, beginning at the time of the morning insulin injection, was significantly (P < 0.05) lower at most blood sampling times in dogs fed if and sf diets, compared with dogs fed the lf diet. As a result, 24-hour mean plasma concentration of glucose (if, 165 ± 17 mg/dl; sf, 169 ± 19 mg/dl; lf, 218 ± 29 mg/dl), 24-hour mean plasma-glucose fluctuation (if, 49 ± 2 mg/dl; sf, 47 ± 4 mg/dl; lf, 63 ± 7 mg/dl), and 24-hour urine-glucose excretion (if, 31 ± 10 g/d; sf, 42 ± 16 g/d; lf, 67 ± 13 g/d) were significantly (P < 0.05) lower in dogs fed if and sf diets, compared with dogs fed the lf diet. These variables were not significantly different between dogs fed if and sf diets. Mean glycosylated hemoglobin concentration also was significantly (P < 0.05) lower when dogs consumed the if diet, compared with the lf diet (4.3 ± 0.4% vs 5.2 ± 0.4%, respectively). In dogs with alloxan-induced insulin-dependent diabetes mellitus, consumption of diets containing 15% cellulose or 15% pectin and > 50% digestible carbohydrate on a dry-matter basis resulted in improvement in glycemic control, compared with consumption of a diet containing > 50% digestible complex carbohydrate without added fiber.

Effect of feeding regimen on diurnal variation of breathing movements in late-gestation fetal sheep

There is a diurnal variation in the mean incidence and amplitude of fetal breathing movements (FBMs) in sheep after approximately 120 days gestation. To determine whether this variation is caused by diurnal fluctuations in plasma glucose or prostaglandin (PG) concentrations, we studied two groups of pregnant sheep fed either once daily at 1100 h or every 2 h for 24 h. Maternal and fetal blood samples were taken every 2 h from 0900 to 0900 h the next day for assay of plasma glucose and PGE2 and PGF2 alpha concentrations. FBMs were recorded throughout the 24 h. The mean fetal plasma glucose concentrations of the once-daily and multifed groups were not different, but there was a significant difference between the two groups in the 24-h pattern of fetal glucose concentrations. In the once-daily fed group, plasma glucose concentrations reached a peak 8 h after maternal feeding and then declined, whereas in the multifed group, fetal plasma glucose concentrations reached a plateau and were constant from 1300 to 0900 h the next day. Fetal plasma PGE2 and PGF2 alpha concentrations did not show a significant change with time of day in either group. There was a significant diurnal variation in the incidence and amplitude of FBMs in each of the two feeding groups, and the 24-h pattern of FBMs did not differ significantly between groups. Therefore it would appear that the diurnal variation of FBMs is not a consequence of the maternal feeding regimen or diurnal changes in plasma glucose or PG concentrations.

Food consumption, plasma glucose and stomach-emptying in insulin-injected hamsters

Two experiments were performed to investigate whether insulin-induced hyperphagia (IIH) serves an adaptive function in counteracting hypoglycemia in hamsters. In Experiment 1, insulin-injected hamsters having free access to food during a six-hour feeding test had neither higher plasma glucose (PG) concentrations nor lower frequencies of neurological impairment at the end of the test than did hamsters whose food intake was restricted to control levels. In Experiment 2, it was observed that PG fluctuations did not act as a trigger for meal-onset in insulin-injected hamsters, nor was PG affected by consumption of a meal during IIH. The withholding of food for periods longer than the typical intermeal interval (IMI) of insulin-injected hamsters (=50 min) resulted in a marked increase in the frequency of neurological deficits among hamsters having PG levels lower than about 40 mg/dl. However animals with similarly low PG concentrations, but deprived of food for less than 50 min showed no signs of impairment, suggesting that some alternate metabolic fuel is available during the IMI and prevents the occurrence of behavioural deficits. The results of these experiments suggest that a simple glucostatic interpretation of IIH in hamsters is inadequate, and although hyploglycemia may play a role in hamster IIH, other factors must also be considered. In Experiment 3, the effect of a hyperphagia-inducing dose of insulin upon stomach emptying was investigated. It was found that both insulin-injected and control hamsters have similar amounts of food in their respective pregastric and gastric pouches at both the onset and offset of meals, but that both pouches empty far more rapidly under the influence of insulin. It is suggested that IIH in hamsters may be dependent in large measure upon the acceleration of stomach emptying, which may in turn depend upon the concomitant hypoglycemia. The exact nature of the hypothesized satiety cues arising from the hamster stomach remains to be investigated.

Dopamine-containing substantia nigra units are unresponsive to changes in plasma glucose levels induced by dietary factors, glucose infusions or insulin administration in freely moving cats

Dopamine-containing neurons in the pars compacta of the substantia nigra showed no significant change in activity during 48 hours of food deprivation in cats that were maintained on either a high carbohydrate diet or a low carbohydrate-high protein diet. Plasma glucose levels declined significantly during this time period in the high carbohydrate diet group, and increased slightly in the low carbohydrate-high protein diet group. In addition, there was no significant change in the activity of dopaminergic neurons in food deprived cats during feeding behavior, during which glucose levels were restored to normal. Intravenous infusion of glucose in freely moving cats, which elevated plasma glucose levels from 82 to 719 mg/100 ml and midbrain glucose from 4.3 to 12.2 μmoles/g, was also without effect on the activity of dopaminergic neurons. Insulin administration to cats maintained on a diet of standard cat chow and fasted for 18 hours decreased plasma and brain glucose to 32.8 mg/100 ml and 2.1 μmoles/g, respectively, but, again, there was no significant change in nigral unit activity. These data demonstrate that central dopaminergic neurons are unresponsive to fluctuations in brain and plasma glucose, and argue against a role for central dopamine systems in the regulation of feeding behavior and energy metabolism.

The importance of determining irreversibly glycosylated hemoglobin in diabetics.

The concentration of glycohemoglobins (HbA1(a+b+c), HbA1,) was measured before and after incubation of normal and diabetic erythrocytes for 6 h at 37°C in saline. This procedure removes as much as 80-90% of the labile glucose-HbA0 adduct (labile HbA1,), thus allowing accurate estimation of irreversibly glycosylated hemoglobin (stable HbA1,). The concentration of HbA1 measured before such an incubation is total HbA1, (stable + labile). We determined the concentration of total, stable, and labile HbA1, in the same blood samples used to measure fasting plasma glucose (FPG) every day, for 4 consecutive days, in two groups of hospitalized insulin-treated diabetics. Group A subjects (N = 7) were type I, C-peptide negative, unstable diabetics, while group B subjects (N = 15) were type II, C-peptide positive, stable diabetics. Individual day-to-day variations of total HbA1, were wide in group A (Δ = 1.58 ± 0.14%), and slight in group B (Δ = 0.12 ± 0.01%; P < 0.001), paralleling similar plasma glucose fluctuations. Day-to-day variations of stable HbA1, were virtually absent not only in group B subjects with stable glycemic values (Δ = 0.08 ± 0.01%), but also in those of group A with marked glycemic instability (Δ = 0.07 ± 0.01%; P = NS). Day-to-day variations of labile HbA1, were marked in group A (Δ = 1.31 ± 0.14%), but negligible in group B (Δ = 0.15 ± 0.03%; P < 0.001). On admission, FPG correlated with labile HbA1, in group A (r = 0.89) and B (r = 0.71). FPG correlated with stable HbA1, in group B (r = 0.73) but not in group A subjects and with total HbA1, more closely in group B (r = 0.73) than in A (r = 0.61). A very close correlation was found between the concentration of total and labile HbA1 in subjects of group B (r = 0.82). In group B, fasting, post-breakfast, and mean daily plasma glucose values, determined every 3-6 days during the 2 mo before admission, significantly correlated both with total and stable HbA1 determined on admission, while in group A they did not. In group A, the correlation was significant when stable instead of total HbA1 was considered. We conclude that the significant fluctuations of total HbA1 reduce its value as an index of long-term control in unstable diabetics. On the other hand, a single determination of stable HbA1, totally independent of simultaneous blood glucose values, closely reflects blood glucose control over the previous 2 mo. We propose routine estimation of stable HbA1, which is simple and straightforward, to carry out follow-up studies of unstable diabetics.

Treatment of juvenile-onset diabetes by subcutaneous infusion of insulin with a portable pump.

We have evaluated the efficacy of an insulin infusion system in the treatment of juvenile-onset diabetic patients that delivers insulin via the subcutaneous route with a portable pump at constant basal rates with pulse dose increments before meals. Studies in the hospital in 15 diabetic patients for 2–14 days indicated rapid restoration of normal glucose homeostasis. Mean plasma glucose levels on pump therapy averaged 85–90 mg/dl, maximal fluctuations in plasma glucose fell by 50–75%, and glycosuria was eliminated. Minimal plasma glucose values varied between 45 and 67 mg/dl. Cholesterol, triglycerides, and free fatty acids as well as fasting and postprandial branched chain amino acid levels were elevated on conventional treatment but fell to normal after 7 days of pump therapy. Pump treatment also restored to normal increased basal growth hormone levels and excessive exercise-induced rises in growth hormone and catecholamines. Normalization of body fuel metabolism occurred, although the total dose of insulin administered by the pump was no greater than the usual insulin dose given by conventional means. We have treated seven insulin-dependent diabetic patients (aged 13–32 yr) for 3–8 mo outside of the hospital. Patients pursued their usual work or school activities. Mean blood glucose (237 ± 28 mg/dl during conventional therapy) fell to 105 ± 5 mg/dl after 4 wk of pump treatment and was maintained between 80 and 104 mg/dl beyond 8 wk. Total glycosylated hemoglobulin was normalized in all patients within 8 wk, as were cholesterol and triglyceride levels. Symptoms of hypoglycemia and overinsulinization and underinsulinization due to human error was relatively uncommon. No episode of mechanical pump failure occurred in 1110 patient-days of use. We conclude that normalization or near normalization of blood glucose levels and correction of abnormal lipid and amino acid metabolism can be achieved with a portable subcutaneous insulin infusion system when continuously used to treat juvenile-onset diabetic patients. Long-term use of this system may provide a feasible means for determining whether metabolic changes resulting from insulin lack cause the complications of diabetes.

Reduction to normal of plasma glucose in juvenile diabetes by subcutaneous administration of insulin with a portable infusion pump.

To improve plasma glucose control, we administered insulin via the subcutaneous route in seven ambulatory patients with juvenile diabetes (12 to 17 years of age), using a portable infusion pump at a basal rate with pulse-dose increments before meals. After two to four days, the mean plasma glucose (+/- 1 S.E.) of 94 +/- 5 mg per deciliter was markedly lower than when insulin was given by conventional methods in the patients' usual dose (243 +/- 28, P less than 0.01) or in a total dose equivalent to that administered with the pump (150 +/- 15, P less than 0.01). Maximal fluctuations in plasma glucose were also 50 to 150 mg per deciliter below those observed with conventional treatment (P less than 0.001). Glycosuria was eliminated in six of seven patients during pump treatment. None of the subjects had hypoglycemia. These results demonstrate that plasma glucose can be lowered to normal in ambulatory patients with brittle juvenile diabetes using a portable, subcutaneous insulin infusion system for two to four days. The feasibility and value of the long-term application of this technic need exploration.