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PubMed1990

Glucose metabolism, second messengers and insulin secretion.

Insulin secretion from beta cells of the islets of Langerhans in the endocrine pancreas is regulated by glucose, glucose metabolites, metabolic intermediates such as ATP, acetyl CoA and reduced pyridine nucleotides, and classical second messengers. Receptor responses transduced by guanine nucleotide binding proteins modulate metabolic activity, the generation of second messengers, and cell depolarization during stimulus-response coupling in the beta cell. This review will consider insulin secretion as regulated by glucose metabolic pathways and second messengers.

Cyclic AMP↗
PubMed2004

Long-term effects of HIV-1 protease inhibitors on insulin secretion and insulin signaling in INS-1 beta cells.

The mechanism by which chronic treatment with HIV (human immunodeficiency virus)-1 protease inhibitors leads to a deterioration of glucose metabolism appears to involve insulin resistance, and may also involve impaired insulin secretion. Here we investigated the long-term effects of HIV-1 protease inhibitors on glucose-stimulated insulin secretion from beta cells and explored whether altered insulin secretion might be related to altered insulin signaling. INS-1 cells were incubated for 48 h with different concentrations of amprenavir, indinavir, nelfinavir, ritonavir or saquinavir, stimulated with 20 mM d-glucose, and insulin determined in the supernatant. To evaluate insulin signaling, cells were stimulated with 100 nM insulin for 2 min, and insulin-receptor substrate (IRS)-1, -2 and Akt phosphorylation determined. Incubation for 48 h with ritonavir, nelfinavir and saquinavir resulted in impaired glucose-induced insulin secretion at 2.5, 5 and 5 microM respectively, whereas amprenavir or indinavir had no effects even at 20 and 100 microM respectively. The impaired insulin secretion by ritonavir, nelfinavir and saquinavir was associated with decreased insulin-stimulated IRS-2 phosphorylation, and, for nelfinavir and saquinavir, with decreased insulin-stimulated IRS-1 and Thr308-Akt phosphorylation. No such effects on signaling were observed with amprenavir or indinavir. In conclusion, certain HIV-1 protease inhibitors, such as ritonavir, nelfinavir and saquinavir, not only induce peripheral insulin resistance, but also impair glucose-stimulated insulin secretion from beta cells. With respect to the long-term effect on beta-cell function there appear to be differences between the protease inhibitors that may be clinically relevant. Finally, these effects on insulin secretion after a 48 h incubation with protease inhibitor were associated with a reduction of the insulin-stimulated phosphorylation of insulin signaling parameters, particularly IRS-2, suggesting that protease inhibitor-induced alterations in the insulin signaling pathway may contribute to the impaired beta-cell function.

Carbamates↗
PubMed2005

CaV2.3 channel and PKClambda: new players in insulin secretion.

Insulin secretion is critically dependent on the proper function of a complex molecular network. Ca(V)2.3-knockout (Ca(V)2.3(-/-)) and PKClambda-knockout (PKClambda(-/-)) mouse models now suggest that these 2 players, the Ca(v)2.3 channel and PKClambda, are important constituents of this molecular network. Subsequent to glucose stimulation, insulin is released from the pancreatic beta cell in a biphasic pattern, i.e., a rapid initial phase followed by a slower, more sustained phase. Interestingly, Ca(2+) influx through the Ca(V)2.3 channel regulates only the second phase of insulin secretion. PKClambda seems to enter the beta cell nucleus and in turn modulates the expression of several genes critical for beta cell secretory function. Studies by Hashimoto et al. and Jing et al. in this issue of the JCI set out to answer the question of why numerous isoforms of proteins with similar functions are present in the beta cell. This is important, since it has been difficult to understand the modulatory and/or regulatory roles of different isoforms of proteins in defined subcellular compartments and at various times during the secretory process in both beta cell physiology and pathophysiology.

Animals↗
PubMed1990

Evaluation of glucose tolerance, insulin secretion, and insulin action in patients with primary hyperparathyroidism before and after surgery.

Glucose tolerance, insulin secretion, and insulin sensitivity were evaluated in 8 asymptomatic patients with primary hyperparathyroidism (PHPT) before and at least 8 weeks after surgical correction of PHPT by means of the hyperglycemic clamp technique. In addition, 15 sex- and age-matched control subjects were investigated for comparative reasons by the same technique. Glucose metabolized (M) during the hyperglycemic clamp was not significantly (NS) different between patients with PHPT and controls (7.9 +/- 2.3 vs. 6.3 +/- 1.9 mg/kg/min). However, insulin secretion (I) was significantly elevated in patients with PHPT compared to controls (87 +/- 17 vs. 45 +/- 12 microU/ml, P less than 0.05). The calculated insulin sensitivity index (M/I) was significantly reduced in PHPT compared to controls (11.0 +/- 2.1 vs. 15.2 +/- 1.4 mg/kg/min per microU/ml x 100, P less than 0.05). Comparing patients with PHPT before and after surgery, the M value, which is a measure of glucose tolerance, was not significantly different (7.9 +/- 2.3 vs. 7.8 +/- 1.5 mg/kg/min). However, insulin secretion was significantly lower after surgical correction of PHPT compared to the preoperative situation (48 +/- 9 microU/ml vs. 87 +/- 17 microU/7 ml, P less than 0.01). The calculated M/I rose significantly after surgery compared to the preoperative value (11 +/- 2.1 vs. 17.6 +/- 2.7 mg/kg/min per microU/ml x 100, P less than 0.001). We conclude that disturbed carbohydrate metabolism, such as insulin hypersecretion and insulin resistance, in patients with PHPT is an early finding in this disease and that these early disturbances in glucose metabolism are, however, fully reversible.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2000

Inhibition of glucose-induced insulin secretion by 4-hydroxy-2-nonenal and other lipid peroxidation products.

Lipid peroxidation due to oxidative stress is accelerated under hyperglycemic conditions such as diabetes mellitus. The effect of 4-hydroxy-2-nonenal (HNE) and other lipid peroxidation products on the ability of isolated rat pancreatic islets to secrete insulin was examined in this study. HNE concentration- and time-dependently deteriorated glucose-induced insulin secretion: insulin secretion was decreased by 50% when measured after incubation of islets with 100 microM HNE for 1 h. Other lipid peroxidation products, e.g. 2-hexenal and 2-butenal, also inhibited glucose-induced insulin secretion. HNE at 100 microM lowered alpha-ketoisocaproate-induced insulin secretion, whereas leucine-induced insulin secretion was stimulated. Insulin secretion induced by 10 mM glyceraldehyde was slightly decreased by HNE. On the other hand, HNE severely decreased insulin secretion induced by 10 mM glyceraldehyde and 2.8 mM glucose. Glucose utilization and glucose oxidation were significantly lowered in islets treated with HNE. The amounts of fructose 1,6-bisphosphate and dihydroxyacetone phosphate in islets were decreased by treatment with HNE, whereas the amount of fructose 6-phosphate was increased. Our study indicates that HNE and other lipid peroxidation products impair insulin secretion induced by glucose probably through affecting both the glycolytic pathway and the citric acid cycle.

Aldehydes↗
PubMed2000

Insulin secretion and insulin sensitivity in diabetic subgroups: studies in the prediabetic and diabetic state.

AIMS/HYPOTHESIS: To evaluate insulin sensitivity and insulin secretion in prediabetic and diabetic subjects with mutations in MODY1 (HNF-4 alpha) and MODY3 (HNF-1 alpha) genes, in subjects with GAD antibodies, latent autoimmune diabetes in adults and in subjects with the common form of Type II (non-insulin-dependent) diabetes mellitus. METHODS: Insulin secretion was measured as the incremental 30-min insulin (I30) and insulin glucose ratio (I:G30) during OGTT whereas insulin sensitivity was measured as the insulin sensitivity index during OGTT in 131 carriers of MODY mutations [NGT = 38, IFG/IGT = 21, diabetes mellitus (DM) = 72], in 293 subjects with GADA (NGT = 47, IFG/IGT = 29, DM = 217) and in 2961 subjects with a family history of the common form of Type II diabetes but without MODY mutations or GADA (NGT = 1360, IFG/IGT = 857, DM = 744). A subgroup of the subjects underwent a euglycaemic clamp (n = 210) and intravenous glucose tolerance test (n = 337) for the estimation of insulin sensitivity and first-phase insulin secretion. RESULTS: Non-diabetic subjects with MODY mutations had pronounced impaired insulin secretion (I30, I:G30) compared with the two other groups (p = 0.005). Normal or non-diabetic glucose tolerance was maintained by enhanced insulin sensitivity compared with the other two groups (p < 0.05 and p < 0.005). In contrast to patients with Type II diabetes and with adult latent autoimmune diabetes, MODY patients showed only a modest deterioration in insulin sensitivity at onset of diabetes. The 2-h glucose values inversely correlated with insulin sensitivity in subjects with GADA (r = -0.447, p < 0.001) and subjects from Type II diabetic families (r = -0.426, p < 0.001), whereas no such relation was observed in subjects with MODY mutations (r = 0.151, p = NS). There were no statistically significant differences in insulin secretion or insulin sensitivity between subjects with GADA or subjects with a family history of Type II diabetes, either at the NGT or the IFG/IGT stage. CONCLUSION/INTERPRETATION: Glucose-tolerant carriers of MODY mutations are characterised by a severe impairment in insulin secretion. Enhanced insulin sensitivity is the most likely explanation for the normal glucose tolerance. Whereas subjects with positive GADA or Type II diabetes have impaired insulin sensitivity with increasing glucose concentrations, MODY mutation carriers seem to be protected from the effect of glucose toxicity.

Adult↗
PubMed2004

[Insulin secretion and insulin sensitivity in 1193 inpatients with essential hypertension].

OBJECTIVE: To evaluate the metabolic profiles of insulin secretion and insulin sensitivity in different categories of nondiabetic patients with essential hypertension, we made a retrospecting study in our hospital. METHODS: According to the criteria of WHO and ADA, we calculated the distribution of plasma glucose levels during a 75 g oral glucose tolerance test (OGTT). Nondiabetic subjects with hypertension were classified into the following four groups: (1) normal glucose tolerance (NGT) with fasting plasma glucose (FPG) < 6.1 mmol/L and 2h-plasma glucose (2hPG) < 7.8 mmol/L, (2) Isolate impaired fasting glucose (IFG) with FPG 6.1-7 mmol/L and 2hPG < 7.8 mmol/L, (3) Isolate impaired glucose tolerance (IGT) with FPG < 6.1 mmol/L and 2hBG 7.8-11.1 mmol/L, (4) impaired fasting glucose and impaired glucose tolerance (IFG/IGT) with FPG 6.1-7 mmol/L and 2hBG 7.8-11.1 mmol/L. Then we divided the groups of NGT and IGT based on the normal 30 or 60 minute plasma glucose level during OGTT respectively. 30 minute plasma glucose level < 11.1 mmol/L and 60 minute plasma glucose level < 10.5 mmol/L were considered to be normal. HOMA-IR (insulin resistance) and composite ISI (insulin sensitivity index) were used to estimate insulin resistance and HOMA-beta and DeltaI/DeltaG index to estimate insulin secretion. RESULTS: 11.1% of the 1193 subjects were newly diagnosed diabetic patients, in whom 57.9% had isolated postchallenge hyperglycemia only. In the IGT and IFG/IGT groups, HOMA-IR were significantly higher than that in the NGT group, whereas composite ISI and DeltaI/DeltaG were significantly lower than that in the NGT group. Whether 30 or 60 minute plasma glucose level was high or not, composite ISI in IGT group was significantly lower than that in the NGT group. In the NGT group, DeltaI/DeltaG in subjects with high 30 or and 60 minute plasma glucose level was significantly lower than that in subjects with normal 30 and 60 minute plasma glucose level. CONCLUSIONS: Subjects with IGT or IFG/IGT have both impaired insulin sensitivity and insulin secretion. In the NGT group, subjects with high 30 or/and 60 minute plasma glucose level have impaired beta-cell function.

Blood Glucose↗
PubMed1995

Effects on glucose tolerance, insulin secretion, insulin-like growth factor 1 and its binding protein, IGFBP-1, in a randomized controlled diet and exercise study in healthy, middle-aged men.

OBJECTIVES: To study the effects of advice on diet, exercise and their combination on oral glucose tolerance (OGTT), insulin secretion, insulin-like growth factor-1 (IGF-1) and its binding protein, IGFBP-1. DESIGN: A 6-month, randomized, controlled intervention study. SETTING: Primary health care centres in Sollentuna, Stockholm and the Department of Medicine, Karolinska Hospital, Stockholm, Sweden. SUBJECTS: One hundred and fifty-seven normoglycaemic healthy men, mean age 46 years, range 35-60 years, with slightly to moderately raised cardiovascular risk factors. INTERVENTIONS: Advice on diet (D, n = 40), exercise (E, n = 39) a combination of both (DE, n = 39) and a control group (C, n = 39). MAIN OUTCOME MEASURES: An OGTT, insulin secretion, IGF-1 and its binding protein, IGFBP-1. RESULTS: The number of pathological OGTTs in the intervention groups decreased from 42/118 to 33/118 whilst the number in the control group did not change. Fasting insulin levels decreased in groups E and DE from 8.8-7.4 mU L-1 (P < 0.01) and from 8.3-6.7 mU L-1 (P < 0.01), respectively. Accordingly, the insulin area under the curve decreased from 5278 to 4828 (P < 0.05) in group E, and from 5482 to 4809 (P < 0.01) in group DE. IGF-1 only increased in group D. The most prominent changes were noted for IGFBP-1, which increased in all three intervention groups and to the highest degree in group DE (from 33.7-42.6 micrograms L-1, P < 0.001). CONCLUSIONS: A combination of increased exercise and improved diet, as well as increased exercise alone, favourably affect glucose and insulin homeostasis in middle-aged men with moderately elevated cardiovascular risk factors. The most marked changes were noted for IGFBP-1, possibly suggesting a decreased insulin secretion and an enhanced insulin sensitivity.

Adult↗
PubMed2000

Pulsatile insulin secretion.

Insulin is secreted in a pulsatile manner. Recently it has been shown that almost all (approximately 70-100%) of insulin is secreted in discrete insulin secretory bursts occurring approximately every 6 min. Furthermore, it has been revealed that regulation of the rate of insulin secretion is achieved primarily through modulation of the mass of these discrete insulin bursts. Thus meal ingestion increases insulin secretion by enhancing insulin burst mass by approximately 50% but also increases pulse frequency by approximately 50%. Interestingly, the hepatic clearance of insulin is also apparently closely related to the pattern of insulin delivery to the liver. It has been known for many years that the pattern of insulin delivery is abnormal in patients with type 2 diabetes. Recently, with new more sensitive insulin assays (ELISA) and validated methods for pulse detection, it has been possible to examine more precisely the abnormalities of pulsatile insulin in patients with type 2 diabetes. These recent studies suggest that the principal defect of insulin secretion is a deficient pulse mass of insulin with no changes in pulse frequency, and that this defect can be overcome by a period of beta cell rest.

Diabetes Mellitus↗
PubMed1984

Effect of islet activating protein on glucose tolerance, insulin secretion and insulin responsiveness in the NZO mouse.

The effect of islet activating protein on glucose tolerance, insulin secretion and insulin responsiveness was studied in the NZO mouse, a model of non-insulin dependent diabetes and obesity. A single IV injection of 5 ng/g body weight islet activating protein markedly lowered plasma glucose and the glucose response to IP glucose administration, measured 5 days later (mean +/- SEM, plasma glucose levels 0, 10, 30 and 60 min after glucose 6.0 +/- 0.9, 14.6 +/- 1.3, 14.1 +/- 1.3 and 13.2 +/- 1.7 mmol/l in islet activating protein-treated NZO mice versus 12.8 +/- 1.6, 27.8 +/- 3.4, 34.7 +/- 4.1, 39.1 +/- 3.8 mmol/l in carrier-treated NZO mice). There was no difference in fasting plasma insulin levels between islet activating protein and carrier-treated mice. No response of plasma insulin to glucose occurred in the carrier-treated mice, but a highly significant insulin response to glucose was seen in the islet activating protein-treated mice. The in vitro responsiveness of pancreatic islets of islet activating protein-treated NZO mice to glucose was improved, and the inhibitory effect of adrenaline on insulin secretion was reduced. The in vivo hypoglycaemic response to exogenous insulin was not improved by islet activating protein and a demonstrated defect in the insulin sensitivity and responsiveness of glucose utilization by isolated soleus muscle was not reversed by islet activating protein treatment. It is concluded that islet activating protein is highly effective in improving glucose tolerance and insulin secretion in NZO mice, and that the improvement in glucose tolerance occurs without demonstrable improvement in the responsiveness to exogenous insulin or sensitivity of soleus muscle to insulin.

Animals↗
PubMed2000

Insulin secretion and insulin sensitivity in relation to glucose tolerance: lessons from the Botnia Study.

Recently, a new stage in glucose tolerance, impaired fasting glucose (IFG) (fasting plasma glucose level of 6.1-6.9 mmol/l), was introduced in addition to impaired glucose tolerance (IGT) (2-h glucose level of 7.8-11.0 mmol/l). It is not clear whether IFG and IGT differ with respect to insulin secretion or sensitivity. To address this question, we estimated insulin secretion (by measuring both insulin levels and the ratio of insulin-to-glucose levels in 30-min intervals) and insulin sensitivity (by using the homeostasis model assessment [HOMA] index) from an oral glucose tolerance test (OGTT) in 5,396 individuals from the Botnia Study who had varying degrees of glucose tolerance. There was poor concordance between IFG and IGT: only 36% (303 of 840) of the subjects with IFG had IGT, whereas 62% (493 of 796) of the subjects with IGT did not have IFG. Compared with subjects with normal glucose tolerance (NGT), subjects with IFG were more insulin resistant (HOMA-insulin resistance [IR] values 2.64 +/- 0.08 vs. 1.73 +/- 0.03, P < 0.0005), had greater insulin responses during an OGTT (P = 0.0001), had higher waist-to-hip ratios (P < 0.005), had higher triglyceride and total cholesterol concentrations (P < 0.0005), and had lower HDL cholesterol concentrations (P = 0.0001). Compared with subjects with IFG, subjects with IGT had a lower incremental 30-min insulin-to-glucose area during an OGTT (13.8 +/- 1.7 vs. 21.7 +/- 1.7, P = 0.0008). Compared with subjects with IGT, subjects with mild diabetes (fasting plasma glucose levels <7.8 mmol/l) showed markedly impaired insulin secretion that could no longer compensate for IR and elevated glucose levels. A progressive decline in insulin sensitivity was observed when moving from NGT to IGT and to subjects with diabetes (P < 0.05 for trend), whereas insulin secretion followed an inverted U-shaped form. We conclude that IFG is characterized by basal IR and other features of the metabolic syndrome, whereas subjects with IGT have impaired insulin secretion in relation to glucose concentrations. An absolute decompensation of beta-cell function characterizes the transition from IGT to mild diabetes.

Adult↗
PubMed1999

Search for variants of the gene-promoter and the potential phosphotyrosine encoding sequence of the insulin receptor substrate-2 gene: evaluation of their relation with alterations in insulin secretion and insulin sensitivity.

AIMS/HYPOTHESIS: The aim of this study was to screen part of the putative promoter sequence in addition to 14 potential phosphotyrosine residues of human IRS-2 for genetic variability which might cause changes in protein expression or function. Furthermore, the potential impact on insulin secretion and sensitivity of a previously identified IRS-2 variant (Gly1057Asp) was analysed. METHODS: The screenings were carried out by the SSCP-heteroduplex technique on DNA from Type II (non-insulin-dependent) diabetic patients. The impact of the Gly1057Asp variant was analysed in four glucose-tolerant Scandinavian study groups. RESULTS: The results showed no nucleotide substitutions in the promoter sequence, however, a novel heterozygous amino acid variant was identified (Leu647Val). In an association study, the new variant was found in 3 of 413 diabetic patients and in none of 280 glucose tolerant subjects. The variant did not affect the binding of IRS-2 to the insulin receptor or p85alpha of phosphatidylinositol 3-kinase when measured in the yeast two-hybrid system. Examination of the common Gly1057Asp variant in 363 young healthy subjects and in 228 glucose tolerant offspring of one diabetic parent showed no differences in insulin secretion or insulin sensitivity after an intravenous glucose tolerance test. Glucose tolerant middle-aged subjects homozygous for the polymorphism (n = 31), however, had on average a 25 % decrease in fasting serum insulin concentrations (p = 0.009) and 28 % (p = 0.01) and 34 % (p = 0.003) reductions in serum insulin concentrations at 30 and 60 min, respectively, during an OGTT compared with wildtype carriers (n = 107). In a cohort of 639 elderly Swedish men the amino acid variant did not have any detectable impact on insulin secretion after an OGTT. CONCLUSION/INTERPRETATION: No genetic variability was found in the IRS-2 promoter. A rare IRS-2 variant at codon 647 has been identified in Type II diabetic patients. The prevalent codon 1057 polymorphism had no consistent effect on insulin secretion or insulin sensitivity. [Diabetologia (1999) 42: 1244-1249]

Adolescent↗
PubMed1999

Insulin secretion and insulin sensitivity in diabetic and non-diabetic subjects with hepatic nuclear factor-1alpha (maturity-onset diabetes of the young-3) mutations.

OBJECTIVE: To evaluate insulin secretion and sensitivity in affected (diabetes mellitus or impaired glucose tolerance; n=7) and in unaffected (normal glucose tolerance; n=3) carriers of hepatocyte nuclear factor-1alpha (maturity-onset diabetes of the young-3 (MODY3)) gene mutations. METHODS: Insulin secretion was assessed by an i.v. glucose tolerance test (IVGTT), hyperglycemic clamp and arginine test, and insulin sensitivity by an euglycemic hyperinsulinemic clamp. Results were compared with those of diabetic MODY2 (glucokinase-deficient) and control subjects. RESULTS: The amount of insulin secreted during an IVGTT was decreased in affected MODY3 subjects (46+/-24 (s.d.) pmol/kg body weight (BW)) as compared with values in MODY2 (120+/-49pmol/kg BW) and control (173+/-37pmol/kg BW; P=0.0004) subjects. The amount of insulin secreted during a 10mmol/l glucose clamp was decreased in affected MODY3 subjects (171+/-78pmol/kg BW) and MODY2 subjects (302+/-104pmol/kg BW) as compared with control subjects (770+/-199pmol/kg BW; P=0.0001). Insulin secretion in response to arginine was decreased in affected MODY3 subjects. Milder and heterogeneous defects were observed in the unaffected MODY3 subjects; the amount of insulin secreted during the hyperglycemic clamp was 40-79% of that of controls. The response to arginine was abnormally delayed. Insulin sensitivity was decreased in diabetic but not in non-diabetic MODY3 subjects. CONCLUSIONS: Beta-cell dysfunction in response to glucose and arginine is observed in affected and unaffected MODY3 subjects. The MODY3 and MODY2 subtypes present different insulin secretion profiles. Secondary insulin resistance might contribute to the chronic hyperglycemia of MODY3 patients and modulate their glucose tolerance.

Adolescent↗
PubMed2000

Maternal diabetes alters birth weight in glucokinase-deficient (MODY2) kindred but has no influence on adult weight, height, insulin secretion or insulin sensitivity.

AIMS/HYPOTHESIS: Altered fetal insulin secretion caused by fetal or maternal glucokinase mutations influence birth weight. Here, we attempt to answer two additional questions: firstly, whether this variation in birth weight (from low birth weight to macrosomia) has an effect on adult height or weight. Secondly, whether maternal hyperglycaemia during fetal life has an effect on metabolic phenotypes of the adult offspring. METHODS: We studied 447 family members from 37 MODY2 kindred, divided into four groups according to the presence or absence of a glucokinase mutation in the subject (S+ or S-, respectively) and his/her mother (M+ or M-). Birth weight data were obtained from a questionnaire sent to the mothers. RESULTS: Birth weight was reduced in the presence of a fetal mutation (M-S+) and increased in the presence of a maternal mutation (M+ S-). These effects are additive as similar birth weights were observed in M+ S+ and M-S- offspring. Adult height, weight or body mass index (weight/height2) were, however, similar in the four groups of subjects. Non-diabetic adult offspring, regardless of the glycaemic status of the mothers (M+ S- or M-S-), had similar insulin secretion, insulin sensitivity, blood pressures and lipid profiles. These variables as well as the severity of hyperglycaemia were similar in adult M+ S+ and M-S+ MODY2 subjects. CONCLUSION/INTERPRETATION: Maternal environment and fetal genotypes could alter growth in utero by changing fetal insulin secretion but these effects do not result in a persistent programming in latter life.

Adolescent↗
PubMed1989

Inhibition of basal insulin secretion induces insulin resistance in normal man: evidence for a tonic effect of insulin on carbohydrate metabolism.

Insulin resistance has been demonstrated both in insulin deficiency and insulin excess in man and in animals. This study was carried out in normal man to evaluate the role of insulinopenia in the pathogenesis of insulin resistance. Insulin suppression was obtained by 4 h somatostatin (SRIF) infusion. Insulin receptors on circulating monocytes were evaluated before and after SRIF infusion; an insulin tolerance test (ITT) was performed after SRIF, saline or SRIF and replacing basal insulin secretion. Insulin binding to circulating monocytes did not change after 4 h insulinopenia (2.19 +/- 0.30 vs. 2.35 +/- 0.80%), while insulin sensitivity appeared decreased after SRIF (KITT = 0.97 +/- 0.13) as compared with saline (KITT = 3.30 +/- 0.42), and this effect was prevented by insulin (KITT = 2.46 +/- 0.38). A relationship was detected between KITT and plasma insulin concentration before ITT (r = 0.85, p less than 0.01), suggesting that insulin deficiency is the main cause of the phenomenon observed. The present data suggest that basal insulin concentration plays an essential role in the control of insulin sensitivity. If insulin binding on monocytes mimics the behavior of major insulin target tissues, it is possible that the impaired insulin action after 4 h of insulin deficiency is related to a post binding effect.

Adult↗
PubMedDate not supplied

Insulin secretion and insulin sensitivity defects are a common feature of mild, clinically homogeneous, recently diagnosed type II (non-insulin-dependent) diabetics.

Alteration in insulin secretion and reduced peripheral sensitivity to the hormone have been reported in type II diabetes. In this paper, a comparison is made of basal glucose production (3H-6 glucose), insulin secretion and insulin sensitivity in vivo (hyperglycemic clamp) and in vitro (binding to circulating monocytes) in 24 patients with recently diagnosed type II diabetes, matched for age and fasting glycemia and divided into non-obese (14 subjects) and moderately obese (10 subjects), and in 9 non-obese controls. The non-obese diabetics were slightly hyperinsulinemic during fasting (10.8 +/- 1.0 vs 4.8 +/- 0.8 microU/ml in controls, p less than 0.0005), with a significant reduction in early and late insulin secretion (14.0 +/- 1.5 vs 20.8 +/- 2.0 microU/ml, p less than 0.01 and 24.8 +/- 3.3 vs 34.7 +/- 2.14 microU/ml, p less than 0.025). The insulin sensitivity index MCR/I was significantly reduced (2.30 +/- 0.32 vs 4.14 +/- 0.40, p less than 0.005). Endogenous glucose production was significantly increased (107 +/- 10.2 vs 84 +/- 3.7 mg/m2 per min, p less than 0.025) and displayed a positive correlation with fasting glycemia (r = 0.51, p less than 0.05). Insulin binding to monocytes was significantly lower than in controls (2.36 +/- 0.22% vs 4.06 +/- 0.32%, p less than 0.0005). Moderately obese diabetics also were significantly hyperinsulinemic in the fasting state (18.1 +/- 2.8 microU/ml, p less than 0.0005 vs controls) but, typically, lacked the early secretory phase (20.6 +/- 3.6 microU/ml vs baseline, n.s.). A similar increase of hepatic glucose production (107 +/- 11.2 mg/m2 per min, p less than 0.025 vs controls, n.s. vs non-obese diabetics) and decrease of peripheral sensitivity to insulin (MCR/I = 1.78 +/- 0.31, p less than 0.0005 vs controls, n.s. vs non-obese diabetics) was found in moderately obese diabetics, as well as a significant reduction of insulin binding to insulated monocytes (2.62 +/- 0.4% p less than 0.01 vs controls, n.s. vs non-obese diabetics). These results confirm that common defects of both non-obese and moderately obese type II diabetics are: lack of early phase of glucose induced insulin secretion, increase in hepatic glucose production and decrease of peripheral insulin sensitivity together with reduction of insulin binding to circulating monocytes. The hypothesis of a unique defect as a cause of hyperglycemia in type II diabetes in early clinical phase is not borne out by the results of this study. Moderate obesity, even if able to reduce insulin sensitivity, seems to be less important in determining hyperglycemia.

Adult↗
PubMed2005

Insulin secretion and insulin sensitivity in Japanese subjects with impaired fasting glucose and isolated fasting hyperglycemia.

Impaired fasting glucose (IFG) is a subgroup of impaired glucose regulation exhibiting an elevated fasting glucose levels without elevated 2-h glucose levels on oral glucose tolerance test (OGTT). Diabetes mellitus with isolated fasting hyperglycemia (DM/IFH) is a similar subgroup of diabetes having higher fasting glucose levels with 2-h glucose levels within the non-diabetic range. The aim of this study is to profile the characteristics of these subgroups to estimate the factors involved in the development from normal glucose tolerance (NGT) via IFG to DM/IFH. Five hundred and sixty seven Japanese males were classified on the basis of 75 g OGTT into four groups, NGT, IFG, DM/IFH, and isolated impaired glucose tolerance (isolated IGT). Insulin secretion was evaluated by insulinogenic index, insulin sensitivity was evaluated by ISI composite, and insulin secretory patterns were compared additionally. IFG and DM/IFH subjects exhibited both lower insulin secretion and lower insulin sensitivity than NGT subjects. There was an insulin peak in NGT, IFG, and DM/IFH at 60 min, which did not occur in isolated IGT. Impaired early-phase and basal insulin secretion and decreased insulin sensitivity both are estimated as factors in progression from NGT via IFG to DM/IFH in these subjects. IFG and DM/IFH subjects have definite fasting hyperglycemia in contrast to isolated IGT subjects, 2-h glucose levels being maintained within the non-diabetic range partly by the insulin peak at 60 min.

Blood Glucose↗
PubMed1983

Effect of age and diet on insulin secretion and insulin action in the rat.

The effects of aging on various aspects of insulin secretion and action were studied in male Sprague-Dawley rats, maintained from 1 1/2 to 12 mo of age on conventional rat chow, sucrose-rich, or calorie-restricted diets. In chow-fed rats, islet volume increased as the animals grew from 1 1/2 to 12 mo of age, but glucose-stimulated insulin secretion (per volume islet) declined over the same interval. In addition, in vivo insulin-stimulated glucose utilization fell in these rats. However, the plasma insulin response to an oral glucose challenge was sufficient to prevent frank decompensation of glucose tolerance (presumably due to an increase in total pancreatic endocrine cell mass). All these changes, with the exception of the decline in glucose-stimulated insulin secretion per volume islet, were accentuated by feeding sucrose. Thus, 12-mo-old sucrose-fed rats had larger islets and higher plasma insulin levels in response to an oral glucose challenge, and the rats were more insulin-resistant than chow-fed rats. However, glucose-stimulated insulin release per volume islet was similar in 12-mo-old chow-fed and sucrose-fed rats. In contrast, calorie restriction led to an amelioration in all but one of the age-related changes, i.e., islets from calorie-restricted rats were comparable in size to those of 2-mo-old rats, the animals had lower plasma insulin levels in response to an oral glucose load, and they were less insulin resistant than the other two groups of 12-mo-old rats. On the other hand, glucose-stimulated insulin secretion per volume islet was similar to that of the other 12-mo-old rats. These results suggest that aging leads to marked changes in both insulin secretion and insulin action. The decline in glucose-stimulated insulin secretion per unit endocrine pancreas appears to be an inevitable consequence of the aging process. In contrast, the age-related changes in islet size, insulin response to a glucose load, and in vivo insulin-stimulated glucose uptake are extremely responsive to variations in amount and kind of calories. DIABETES 32:175-180, February 1983.

Aging↗