Biomedical subjects

D Porte

Publications and source records attributed to D Porte.

At least 73 records · Page 4Linked to original sources

PubMed1991

Central insulin administration reduces neuropeptide Y mRNA expression in the arcuate nucleus of food-deprived lean (Fa/Fa) but not obese (fa/fa) Zucker rats.

By acting in the brain, insulin suppresses food intake, whereas neuropeptide Y (NPY) has the opposite effect. Since fasting increases NPY gene expression in the hypothalamic arcuate nucleus (ARC) and also lowers circulating insulin levels, we hypothesized that the anorexiant effect of insulin could result from insulin inhibition of NPY gene transcription in the ARC. Therefore, we determined whether the administration of insulin (200 mU per 12 hrs) into the 3rd cerebral ventricle of lean (Fa/Fa) female Zucker rats (n = 5) during 48 hrs of food deprivation reduces the expression of preproNPY mRNA in the ARC compared to vehicle-treated controls (n = 5). Coronal sections of rat brain were hybridized with an oligonucleotide probe complementary to preproNPY mRNA and apposed to x-ray film. Hybridization was quantified in both the ARC and the hippocampal dentate gyrus by computerized image analysis of the resulting autoradiographs. Central insulin significantly reduced the area of hybridization in the ARC (0.235 +/- 0.017 mm2; mean +/- SE) compared to vehicle-treated controls (0.331 +/- 0.037 mm2; p less than 0.05), but was without effect in the hippocampus. Thus, insulin reduced the expression of mRNA for NPY specifically in the ARC. Since the genetically obese (fa/fa) Zucker rat is insensitive to the anorexiant effect of insulin and over-expresses NPY in the ARC, we next tested the hypothesis that insulin does not suppress NPY mRNA expression in the ARC of these rats. Consistent with this hypothesis, central insulin administration to obese Zucker rats during 48 hrs of food deprivation (n = 6) did not lower hybridization area in the ARC compared to vehicle alone (n = 4) (0.286 +/- 0.036 vs. 0.248 +/- 0.019 mm2; p greater than 0.05). We conclude that insulin suppresses the expression of mRNA for NPY in the ARC of fasted lean but not obese Zucker rats. Regulation of hypothalamic NPY gene expression by insulin may account for its anorexiant effect, and a defect in this action may contribute to certain forms of obesity.

Animals↗

PubMed1991

Localization of type I insulin-like growth factor receptor messenger RNA in the adult rat brain by in situ hybridization.

Using multiple 35S-labeled oligonucleotide probes concurrently, the type I insulin-like growth factor receptor (IGF-I-R) mRNA was demonstrated by Northern blot hybridization in newborn and adult rat brain as a single species of approximately 11 kilobases. The probes were used to localize IGF-I-R mRNA by in situ hybridization in slices of adult rat brain. The highest levels of IGF-I-R mRNA expression were found in the glomerular and mitral cell body layers of the olfactory bulb, the granule cell body layers of the dentate gyrus and cerebellum, the pyramidal cell body layers of the piriform cortex and Ammon's horn, and the choroid plexus. The lowest levels of IGF-I-R mRNA expression were found in white matter. At the cellular level, IGF-I-R mRNA was expressed by a variety of neurons, by epithelial cells of the choroid plexus, and by ependymal cells of the third ventricle. Of the neuron types studied, the highest levels of IGF-I-R mRNA were consistently found in perikarya of mitral and tufted cells in the olfactory bulb, in pyramidal cells of the piriform cortex and Ammon's horn, and in granule cells of the dentate gyrus. There was a close congruency between the distribution of IGF-I binding and IGF-I-R mRNA at the regional level. Neuropil layers in the cerebral cortex, olfactory bulb, hippocampus, and cerebellum contained a high level of IGF-I binding, whereas the adjacent cell body layers contained a high level of the IGF-I-R mRNA. We conclude that in these regions, IGF-I-R mRNA is synthesized in neuronal cell bodies, and the receptors are transported to axons and dendrites in adjacent synapse-rich layers, where appropriate IGF effects are achieved.

Animals↗

PubMed1991

Banting lecture 1990. Beta-cells in type II diabetes mellitus.

In 1960, immunoassays of insulin first demonstrated significant quantities of circulating hormone in non-insulin-dependent (type II) diabetes and for 30 yr have fostered debate as to whether a beta-cell abnormality plays an etiological role in this syndrome. Early efforts to determine the adequacy of islet beta-cell function showed that obesity and its associated insulin resistance were major confounding variables. Subsequently, it was recognized that glucose not only directly regulated insulin synthesis and secretion but moderated all other islet signals, including other substrates, hormones, and neural factors. When both obesity and glucose are taken into account, it becomes clear that patients with fasting hyperglycemia all have abnormal islet function. Type II diabetes is characterized by a defect in first-phase or acute glucose-induced insulin secretion and a deficiency in the ability of glucose to potentiate other islet nonglucose beta-cell secretagogues. The resulting hyperglycemia compensates for the defective glucose potentiation and maintains nearly normal basal insulin levels and insulin responses to nonglucose secretagogues but does not correct the defect in first-phase glucose-induced insulin release. Before the development of fasting hyperglycemia, only first-phase glucose-induced insulin secretion is obviously defective. This is because progressive islet failure is matched by rising glucose levels to maintain basal and second-phase insulin output. The relationship between islet function and fasting plasma glucose is steeply curvilinear, so that there is a 75% loss of beta-cell function by the time the diagnostic level of 140 mg/dl is exceeded. This new steady state is characterized by glucose overproduction and inefficient utilization. Insulin resistance is also present in most patients and contributes to the hyperglycemia by augmenting the glucose levels needed for compensation. Decompensation and absolute hypoinsulinemia occur when the renal threshold for glucose is exceeded and prevents further elevation of circulating glucose. The etiology of the islet beta-cell lesion is not known, but a hypothesis based on basal hyperproinsulinemia and islet amyloid deposits in the pancreas of type II diabetes is reviewed. The recent discovery of the islet amyloid polypeptide (IAPP) or amylin, which is the major constituent of islet amyloid deposits, is integrated into this hypothesis. It is suggested that pro-IAPP and proinsulin processing and mature peptide secretion normally occur together and that abnormal processing, secondary to or in conjunction with defects in hormone secretion, lead to progressive accumulation of intracellular IAPP and pro-IAPP, which in cats, monkeys, and humans form intracellular fibrils and amyloid deposits with a loss of beta-cell mass.(ABSTRACT TRUNCATED AT 400 WORDS)

Diabetes Mellitus, Type 2↗

PubMed1990

Islet function and insulin sensitivity in the non-diabetic offspring of conjugal type 2 diabetic patients.

To determine whether the genetic predisposition towards Type 2 diabetes was associated with a defect in either islet-cell function or insulin action, 12 non-diabetic offspring each of whose parents both had Type 2 diabetes were studied, together with 12 control subjects matched for age, sex, and weight. Fasting plasma glucose was higher in the offspring (5.5 +/- 0.1 mmol l-1 (mean +/- SE)) than in the matched controls (5.1 +/- 0.1 mmol l-1) (p less than 0.05). Using an IVGTT insulin sensitivity was not significantly lower in the offspring compared with their controls (3.1 +/- 0.5 vs 3.8 +/- 1.0 min-1 mU-1 l 10(-4)). There was no significant difference in any of the measures of insulin secretion (first- and second-phase response to IV glucose, slope of glucose potentiation, and maximal glucose regulated insulin secretory capacity). Glucagon secretion measured before and after a stimulus of IV arginine at varying plasma glucose concentrations was virtually identical in the offspring and their controls. Among a total of 28 non-diabetic subjects of differing body-weights there was a significant inverse relationship between insulin sensitivity and insulin secretion. When adjusted for their generally lower insulin sensitivity, maximal insulin secretory capacity was reduced in the offspring (p = 0.038, one-tailed t-test). The results suggest that the genetic predisposition to Type 2 diabetes is not associated in young adults with any major pre-morbid impairment in insulin secretion or insulin action but the relationship between the two may be abnormal. Islet A-cell function appears to be normal.

Adult↗

PubMed1990

Kinetics and specificity of insulin uptake from plasma into cerebrospinal fluid.

To characterize the relationship between insulin levels in plasma and those in cerebrospinal fluid (CSF), we studied the kinetics of both the uptake of insulin into CSF from plasma and the turnover of insulin within the CSF compartment. Sustained physiological levels of euglycemic hyperinsulinemia (plasma insulin approximately 500 pM) did not alter CSF insulin levels within the 1st h, but by 90 min a significant increase was observed (P less than 0.01). During graded hyperinsulinemic clamps (mean plasma insulin approximately 500-15,000 pM), CSF insulin rose in a dose-dependent fashion. This rise was characterized by an initial delay followed by a continuous increase for the next 150 min. We also found that after brief, high-dose intravenous insulin infusions, the t1/2 of CSF insulin was 143 +/- 7 min (means +/- SE; n = 4), similar to that of CSF turnover by bulk flow. To test the specificity of CSF insulin uptake from plasma, we compared this uptake during intravenous insulin infusions with that of proinsulin, a peptide with reduced affinity for the insulin receptor. We observed a significantly lower increment of CSF proinsulin levels over 180 min (13.6 +/- 1.6 pM; means +/- SE; n = 4) compared with that of insulin (22.4 +/- 0.6 pM; n = 4; P less than 0.01), despite plasma proinsulin levels higher than insulin (1,890 +/- 287 vs. 1,283 +/- 192 pM; P less than 0.001). When corrected for the difference in plasma levels, the uptake of insulin was fivefold greater than that of proinsulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Evidence for separate receptors for insulin and insulin-like growth factor-I in choroid plexus of rat brain by quantitative autoradiography.

Binding of insulin and insulin-like growth factor-I (IGF-I) to the choroid plexus was quantitatively characterized using autoradiography and computer densitometry. Slide-mounted brain slices were incubated in 0.1 nM [125I]-insulin or [125I]-[Thr59]IGF-I. To determine specificity of the binding sites, the labeled peptides were mixed with unlabeled analogues. Autoradiography was done with LKB Ultrofilm and analyzed with a computer image analysis system and program for densitometry. Results showed that binding was time and temperature dependent and reversible. Binding of the iodinated insulin and IGF-I was inhibited by unlabeled peptides in a dose-dependent manner. The rank order of potency of these peptides in competing for the choroid plexus iodoinsulin binding sites was: chicken insulin greater than porcine insulin greater than desoctapeptide insulin greater than IGF-I. IGF-I was more potent than porcine insulin in competing for the choroid plexus iodolGF-I binding sites. Somatostatin was ineffective. Non-linear regression analysis revealed the presence of high- (Kd 1.3 +/- 0.2 nM) and low-affinity (Kd 36 +/- 1.4 nM) binding sites for insulin and a single high-affinity binding site (Kd 3.1 +/- 0.3 nM) for IGF-I in the choroid plexus. There were approximately 50 times more binding sites (Bmax) for IGF-I than for insulin high-affinity sites, whereas the number of low-affinity sites for insulin was about equal to the number of IGF-I high-affinity sites. The results of these binding studies with iodinated insulin and [Thr59]IGF-I support the conclusion that the rat choroid plexus has separate high-affinity receptors for insulin and IGF-I, and that the IGF-I receptors outnumber the insulin receptors.

Animals↗

PubMed1990

Localization of insulin receptor mRNA in rat brain by in situ hybridization.

Insulin receptor mRNA was demonstrated in rat brain slices by in situ hybridization with three 35S-oligonucleotide probes and contact film autoradiography. Specificity was confirmed by showing that (a) excess unlabeled probe abolished the signal, (b) an oligonucleotide probe for rat neuropeptide Y mRNA showed a different distribution of hybridization signal, and (c) the distribution of insulin receptor binding was consistent with the distribution of insulin receptor mRNA. Insulin receptor mRNA was most abundant in the granule cell layers of the olfactory bulb, cerebellum and dentate gyrus, in the pyramidal cell body layers of the pyriform cortex and hippocampus, in the choroid plexus and in the arcuate nucleus of the hypothalamus.

Animals↗

PubMed1990

Disproportionately elevated proinsulin in Pima Indians with noninsulin-dependent diabetes mellitus.

Fasting serum total immunoreactive insulin (IRI), true insulin, and true proinsulin (PI) were measured in 169 Pima Indians. The relationship of these variables to glucose tolerance, obesity, and parental diabetes was studied. Seventy-seven subjects had normal glucose tolerance, 46 had impaired glucose tolerance (IGT), and 46 had noninsulin-dependent diabetes mellitus (NIDDM) by WHO criteria. In subjects with normal glucose tolerance, the geometric mean ratio of PI to IRI (PI/IRI) was 10.8% (arithmetic mean, 12.5%), similar to that reported in other ethnic groups with lower prevalence rates of NIDDM. Parental diabetes had no effect on PI/IRI. Obese persons (body mass index, greater than or equal to 27 kg/m2) with normal glucose tolerance had PI/IRI of 9.3% compared with 16.3% for the nonobese (P less than 0.001), and PI/IRI was negatively correlated with body mass index (r = -0.34; P = 0.002). Proinsulin was disproportionately elevated in NIDDM (geometric mean PI/IRI, 19.9%; arithmetic mean, 23.6%), and the degree of elevation was related to the severity of hyperglycemia, but not the duration of diabetes. Subjects with IGT were more obese and had higher fasting plasma glucose (5.7 vs. 5.2 mmol/L; P = 0.025), true insulin (250 vs. 125 pmol/L; P less than 0.001), and PI concentrations (26 vs. 15 pmol/L; P less than 0.001) than those with normal glucose tolerance but similar mean PI/IRI (9.4 vs. 10.8%; P = 0.4). These findings indicate that Pima Indians with NIDDM have a disproportionate elevation of PI consistent with the hypothesis that beta-cell dysfunction associated with hyperglycemia leads to the release of proinsulin-rich immature granules.

Adolescent↗

PubMed1990

Treatment with a somatostatin analog decreases pancreatic B-cell and whole body sensitivity to glucose.

To determine the specific alteration in B-cell function caused by a somatostatin analog in man and to determine the effect of the induced insulin deficiency on insulin action, we administered octreotide (SMS 201-995; 50 micrograms twice daily) to nine healthy male subjects, aged 24-35 yr. B-Cell function was assessed by measuring the acute insulin response (AIR) to glucose (AIRglucose) at fasting glucose and to arginine (AIRarg) at glucose concentrations of fasting, approximately 14 and more than 28 mM after 2 (n = 7) and 8 days (n = 9) of octreotide. The AIRarg at more than 28 mM glucose (AIR500) is an estimate of B-cell secretory capacity, while the glucose level at which 50% of AIR500 occurs is termed PG50 and can provide an estimate of B-cell glucose sensitivity. Insulin sensitivity and the parameters describing glucose disposal were measured using Bergman's minimal model. Octreotide administration resulted in the development of mild fasting hyperglycemia, marked fasting hypoinsulinemia, as well as a marked reduction in AIRglucose [mean +/- SE; pretreatment, 260 +/- 48 pM; 1 day, 62 +/- 14 pM (P less than 0.005 vs. pretreatment); 8 days, 62 +/- 7 pM (P less than 0.005 vs. pretreatment)]. In addition, there was an associated marked reduction in iv glucose tolerance. While the AIRarg at fasting glucose (pretreatment, 233 +/- 27 pM; 2 days, 144 +/- 27 pM; 8 days 281 +/- 55 pM) and AIR500 (pretreatment 1000 +/- 178 pM; 2 days, 651 +/- 82 pM; 8 days, 1041 +/- 219 pM) remained unchanged, the AIRarg at 14 mM decreased significantly during octreotide [pretreatment 986 +/- 178 pM; 2 days, 363 +/- 62 pM (P less than 0.001 vs. pretreatment); 8 days, 623 +/- 130 pM (P less than 0.005 vs. pretreatment)], resulting in a rightward shift of the dose-response curve such that the estimated PG50 increased from 8.8 +/- 0.6 to 12.9 +/- 1.3 mM (P less than 0.05) after 2 days and was maintained for 8 days (11.2 +/- 0.8 mM; P less than 0.05 vs. pretreatment). Despite the development of marked insulin deficiency, the insulin sensitivity index (SI) did not change significantly (pretreatment, 11.34 +/- 1.59 x 10(-5); 1 day, 10.01 +/- 2.28 x 10(-5); 7 days, 9.65 +/- 1.69 x 10(-5) min-1/pM).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1990

Evidence of cosecretion of islet amyloid polypeptide and insulin by beta-cells.

Islet amyloid polypeptide (IAPP) has been identified as the major constituent of the pancreatic amyloid of non-insulin-dependent diabetes mellitus (NIDDM) and is also present in normal beta-cell secretory granules. To determine whether IAPP is a pancreatic secretory product, we measured the quantity of IAPP-like immunoreactivity (IAPP-LI), insulin, and glucagon released into 5 ml of incubation medium during a 2-h incubation of monolayer cultures (n = 5) of neonatal (3- to 5-day-old) Sprague-Dawley rat pancreases under three conditions: 1.67 mM glucose, 16.7 mM glucose, and 16.7 mM glucose plus 10 mM arginine and 0.1 mM isobutylmethylxanthine (IBMX). The quantity of IAPP-LI, insulin, and glucagon in the cell extract was also determined. Mean +/- SE IAPP-LI in the incubation medium increased from 0.041 +/- 0.003 pmol in 1.67 mM glucose to 0.168 +/- 0.029 pmol in 16.7 mM glucose (P less than 0.05) and 1.02 +/- 0.06 pmol in 16.7 mM glucose plus arginine and IBMX (P less than 0.05 vs. 1.67 or 16.7 mM glucose). Insulin secretion increased similarly from 4.34 +/- 0.27 to 20.2 +/- 0.6 pmol (P less than 0.05) and then to 135 +/- 5 pmol (P less than 0.05 vs. 1.67 or 16.7 mM glucose). Glucagon release tended to decrease with the increase in glucose concentration (0.39 +/- 0.01 vs. 0.33 +/- 0.02 pmol, P less than 0.1), whereas with the addition of arginine and IBMX to high glucose, glucagon release increased to 1.32 +/- 0.03 pmol (P less than 0.05 vs. 1.67 or 16.7 mM glucose).(ABSTRACT TRUNCATED AT 250 WORDS)

Amyloid↗

PubMed1990

A re-assessment of the regulation of adiposity and appetite by the brain insulin system.

We have provided strong support for the hypothesis that the pancreatic hormone, insulin, provides a signal to the brain indicating the level of adiposity. Because insulin is found in the cerebrospinal fluid (CSF) in direct proportion to plasma levels, and because changes of plasma insulin result in subsequent changes of CSF insulin, we previously hypothesized that the blood-borne insulin signal enters the central nervous system by initially entering the CSF and then diffuses into the brain. Such a route explained the time lag for influences of insulin upon food intake and body weight. Recent evidence suggests that insulin may enter the brain directly through brain capillaries, raising the possibility that what is measured in the CSF may not be indicative of insulin on its way into critical brain areas. Implications of this change of route of entry of insulin into the brain for the regulation of food intake and body weight are discussed.

Adipose Tissue↗

PubMed1989

IVT CCK-8 is more effective than IV CCK-8 at decreasing meal size in the baboon.

In this study, we compared the effectiveness of intravenous (IV) vs. intraventricular (IVT) cholecystokinin octapeptide (CCK-8) to decrease single meal size over a dose range of 0.1 to 4.0 micrograms/kg in a population of overnight fasted baboons. IV CCK did not decrease meal size significantly at doses of 0.5, 1, and 4 micrograms/kg (84 +/- 22%, 78 +/- 12%, and 89 +/- 33% of paired control meal sizes respectively). IVT CCK significantly decreased single meal size at all doses tested (40 +/- 18%, 26 +/- 10%, 37 +/- 15%, 26 +/- 12%, and 12 +/- 6% of paired control meal sizes at 0.1, 0.25, 0.5, 1, and 2 micrograms/kg respectively). Meal suppression with IVT CCK was significantly greater than that achieved with IV CCK at doses of 1 and 2 micrograms/kg. We conclude that in the baboon, CCK may have a direct effect at the central nervous system to suppress single meal size.

Animals↗

PubMed1989

Intraventricular CCK inhibits food intake and gastric emptying in baboons.

To evaluate the role of cholecystokinin (CCK) as a physiological regulator of meal size and gastric emptying in the baboon, we measured plasma CCK bioactivity during 30-min meals alone and after intravenous or intraventricular infusions of CCK COOH-terminal octapeptide (CCK-8). Both intravenous (2 micrograms/kg) and intraventricular (1 microgram/kg) CCK-8 administration resulted in plasma CCK elevations comparable with normal prandial CCK levels: peak plasma levels were 4.1 +/- 0.9, 7.1 +/- 1.1, and 4.9 +/- 2.2 pM for pooled intravenous and intraventricular control, intravenous, and intraventricular conditions. Also, both treatments appeared to reduce gastric emptying as indicated by a significant suppression of postprandial plasma insulin and glucose levels. However, only intraventricular CCK reliably reduced meal size (percent of control meal size was 91 +/- 5% or 43 +/- 19% with intravenous or intraventricular CCK). We conclude that circulating endogenous CCK is a potent postprandial endocrine regulator of gastric emptying. However, the ability of CCK to decrease meal size may require direct interaction with the central nervous system.

Animals↗

PubMed1989

Hyperproinsulinemia and amyloid in NIDDM. Clues to etiology of islet beta-cell dysfunction?

Impaired islet function is a feature of non-insulin-dependent diabetes mellitus (NIDDM), which is manifested in part by disproportionate proinsulin release. A disproportionate increase in proinsulin also occurs in insulinomas, suggesting that enhanced proinsulin release results from an increase in synthesis and premature release of proinsulin-rich immature granules in both conditions. However, recent human and animal studies suggest that normal beta-cells respond to an increase in synthetic demand by enhancing their ability to process proinsulin. Thus, impaired processing of proinsulin is likely in NIDDM. A new point of similarity with insulinoma has been the demonstration of a novel pancreatic peptide isolated from insulinomas and the pancreas of patients with NIDDM. This peptide, named islet amyloid polypeptide or amylin, is also present in normal islets. Because of its association with two apparently dissimilar disease states, we propose a hypothesis that encompasses the observations related to proinsulin and islet amyloid polypeptide and suggest they are manifestations of the same abnormality. In this hypothesis, we suggest that this new pancreatic peptide is a normal participant in the process of proinsulin processing and storage. We also suggest that in the presence of defective proinsulin processing and insulin release, as occurs in NIDDM, hyperglycemia stimulates amylin biosynthesis so that this peptide is deposited in increased quantities in the islet as amyloid. This then further exacerbates the diabetic process, resulting in progressive hyperglycemia and deterioration in islet function.

Amyloid↗

PubMed1989

Increased beta-cell secretory capacity as mechanism for islet adaptation to nicotinic acid-induced insulin resistance.

To determine whether prolonged nicotinic acid (NA) administration produces insulin resistance and, if so, how the normal pancreatic islet adapts to prolonged insulin resistance, we administered incremental doses of NA to 11 normal men for 2 wk, ending at 2 g/day. Insulin sensitivity was measured with Bergman's minimal model. Islet function was evaluated by measurement of acute insulin (AIR) and glucagon (AGR) responses to arginine at three glucose levels. Insulin resistance was demonstrated and quantified by a marked drop in the insulin sensitivity index (Sl) from 6.72 +/- 0.77 to 2.47 +/- 0.36 x 10(-5) min-1/pM (P less than .0001) and resulted in a doubling of basal immunoreactive insulin levels (from 75 +/- 7 to 157 +/- 21 pM, P less than .001) with no change in fasting glucose (5.5 +/- 0.1 vs. 5.7 +/- 0.1 mM). Proinsulin levels also increased (from 9 +/- 1 to 15 +/- 2 pM, P less than .005), but the ratio of proinsulin to immunoreactive insulin did not change (12.7 +/- 1.9 vs. 10.3 +/- 1.9%). beta-Cell changes were characterized by increases in the AIR to glucose (from 548 +/- 157 to 829 +/- 157 pM, P less than .005) and in the AIR to arginine at the fasting glucose level (from 431 +/- 54 to 788 +/- 164 pM, P less than .05). At the maximal hyperglycemia level the AIR to arginine represents beta-cell secretory capacity, and this increased with administration of NA (from 2062 +/- 267 to 2630 +/- 363 pM, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1988

Islet dysfunction in non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus is characterized by fasting hyperglycemia associated with defects in the pancreatic islet, the liver, and the peripheral tissues, which together comprise a feedback loop responsible for maintenance of glucose homeostasis. This review focuses on the key role of the endocrine pancreas A and B cells to coordinate glucose output from the liver with glucose utilization. The basal rate of hepatic glucose production is elevated in subjects with non-insulin-dependent diabetes mellitus and this is positively correlated with the degree of fasting hyperglycemia. This increased rate of glucose release by the liver results from impaired hepatic sensitivity to insulin and reduced insulin secretion. Though basal insulin levels in patients with non-insulin-dependent diabetes mellitus may appear normal when compared with those of healthy persons, islet function testing at matched glucose levels reveals impairments of basal and stimulated insulin secretion due to a reduction in B cell secretory capacity. The degree of impaired beta-cell responsiveness to glucose is closely related to the degree of fasting hyperglycemia but in a curvilinear fashion. The efficiency of glucose uptake by the peripheral tissues is also impaired due to a combination of decreased insulin secretion and defective cellular insulin action. This impairment becomes more important to the hyperglycemia as the islet dysfunction declines. Therapeutic interventions either improve islet dysfunction and raise plasma insulin levels, reduce hepatic glucose production, or improve the efficiency of tissue glucose uptake. All result in a decline in the fasting glucose level regardless of the cause of hyperglycemia. It is concluded that non-insulin-dependent diabetes mellitus is characterized by a steady-state re-regulation of plasma glucose concentration at an elevated level in which islet dysfunction plays a necessary role.

Blood Glucose↗

PubMed1988

Insulin responses and glucose levels in plasma and cerebrospinal fluid during fasting and refeeding in the rat.

The present experiments were designed to investigate the rate of penetration of insulin from the plasma into the cerebrospinal fluid (CSF) during 24 hr of fasting and refeeding in the light phase. The results show that under these conditions basal CSF-immunoreactive insulin (IRI) levels were positively correlated with plasma IRI levels. Basal plasma IRI fell during a fast but was similar to prefast control after one day of refeeding. Although CSF-IRI levels rose during glucose infusion, CSF-IRI was not elevated by glucose during a fast. During refeeding, CSF-IRI responses returned toward control, prefeeding values. This study suggests a decreased transport of insulin from plasma to CSF during fasting. The lower CSF-IRI levels achieved under these conditions may determine meal size by allowing larger meals after a fast.

Animals↗

PubMed1988

Penetration of peripheral glucose and insulin into cerebrospinal fluid in rats.

In this study the penetration of plasma insulin and glucose into the cerebrospinal fluid (CSF) was investigated. Rats were implanted with cannulas in the cisterna magna and into the left and right jugular veins. Freely moving rats were intravenously infused during 4 h with either glucose solution (10 mg/min) or saline. Before, during, and after the infusions, simultaneous blood and CSF samples were taken. Infusion of glucose led to an immediate rise of both plasma glucose and insulin. Although CSF glucose followed plasma glucose within 10 min, CSF insulin was unchanged until 40 min. After termination of the glucose infusion, levels of all substances returned to base line within 10 min. Twenty-four-hour food deprivation resulted in a significant decrease of plasma glucose, plasma insulin, CSF glucose, and CSF insulin. At the onset of eating after deprivation, an increase of plasma glucose and insulin occurred within 10 min, whereas CSF glucose was delayed between 10 and 40 min, after which ad libitum values were attained or surpassed. CSF insulin always remained below ad libitum levels. It is concluded that 1) glucose and insulin penetrate into the CSF and 2) CSF insulin and glucose can fulfill a putative feedback in homeostatic control of food intake and body weight.

Animals↗