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S E Kahn

Publications and source records attributed to S E Kahn.

At least 73 records · Page 4Linked to original sources
PubMed1996

Insulin transport from plasma into the central nervous system is inhibited by dexamethasone in dogs.

We have previously shown that transport of plasma insulin into the central nervous system (CNS) is mediated by a saturable mechanism consistent with insulin binding to blood-brain barrier insulin receptors and subsequent transcytosis through microvessel endothelial cells. Since glucocorticoids antagonize insulin receptor-mediated actions both peripherally and in the CNS, we hypothesized that glucocorticoids also impair CNS insulin transport. Nine dogs were studied both in the control condition and after 7 days of high-dose oral dexamethasone (DEX) administration (12 mg/day) by obtaining plasma and cerebrospinal fluid (CSF) samples over 8 h for determination of immunoreactive insulin levels during a 90-min euglycemic intravenous insulin infusion (plasma insulin approximately 700 pmol/l). From these data, the kinetics of CNS insulin uptake and removal were determined using a mathematical model with three components (plasma-->intermediate compartment, hypothesized to be brain interstitial fluid-->CSF). DEX increased basal insulin levels 75% from 24 +/- 6 to 42 +/- 30 pmol/l (P < 0.005) and slightly increased basal glucose levels from 5.0 +/- 0.7 to 5.3 +/- 1.0 mmol/l (P < 0.05). DEX also lowered the model rate constant characterizing CNS insulin transport by 49% from 5.3 x 10(-6) +/- 4.0 x 10(-6) to 2.7 x 10(-6) +/- 1.2 x 10(-6) min-2 (P < or = 0.001). As glucocorticoids are known to reduce CSF turnover, we also hypothesized that the model rate constant associated with CSF insulin removal would be decreased by DEX. As expected, the model rate constant for CSF insulin removal decreased 47% from 0.038 +/- 0.013 to 0.020 +/- 0.088 min-1 (P < or = 0.0005) during DEX treatment. We conclude that DEX impairs CNS insulin transport. This finding supports our hypothesis that insulin receptors participate in the CNS insulin transport process and that this process may be subject to regulation. Moreover, since increasing brain insulin transport reduces food intake and body adiposity, this observation provides a potential mechanism by which glucocorticoid excess leads to increased body adiposity.

Animals↗
PubMed1996

Nicotinamide's effects on glucose metabolism in subjects at risk for IDDM.

Nicotinamide is being used in trials to prevent or delay the development of clinical IDDM. A related compound, niacin, has been shown to cause insulin resistance in normal subjects, resulting in increased insulin secretion. This study was designed to answer the question: Does the short-term administration of nicotinamide cause insulin resistance in subjects who have a high risk of developing IDDM? Eight islet cell antibody-positive (ICA+) relatives of IDDM patients were given nicotinamide at a dose of 2 g/day for 2 weeks. Measurements of first-phase insulin release, insulin sensitivity, glucose effectiveness, and the constant for glucose disappearance (Kg) were measured at baseline, at the end of 2 weeks of therapy, and after subjects had been off therapy for at least 2 weeks. Nicotinamide administration caused a 23.6% decrease in insulin sensitivity (P = 0.02). This decrease was associated with a fall in Kg despite increased insulin secretion. Our data suggest that the use of nicotinamide in subjects who are at risk of developing IDDM may be complicated by the drug's effects on insulin sensitivity. By inducing insulin resistance, a therapeutic effect of nicotinamide on the diabetes disease process may be missed, and the interpretation of insulin secretion measurements that are obtained during the intervention trials using nicotinamide may be complicated by the changes in insulin secretion that are caused by the increased insulin resistance. Therefore, we strongly support the recommendation that at least one subgroup of subjects enrolled in clinical trials to prevent IDDM have regular measurements of both insulin sensitivity and insulin secretion performed. This subgroup should be randomly assigned and large enough for statistical analysis to interpret properly the changes in insulin secretion that may occur.

Adult↗
PubMed1996

A variation at position -30 of the beta-cell glucokinase gene promoter is associated with reduced beta-cell function in middle-aged Japanese-American men.

We sought to determine whether a G -> A variant at position -30 of the beta-cell promoter of the glucokinase (GCK) gene observed to be present more frequently in Japanese-American men with impaired glucose tolerance (IGT) than in Japanese-American men with normal glucose tolerance (NGT) is associated with impaired beta-cell function. We studied 125 unrelated Japanese-American men (aged 46-74 years; mean 61 +/- 0.5) who were nondiabetic by a 75-g oral glucose tolerance test (OGTT) (65 had NGT and 60 had IGT). The presence of the -30 beta-cell GCK gene promoter variant was determined by single-strand conformation polymorphism analysis. Beta-cell function was assessed using the ratio of the incremental response in immunoreactive insulin (IRI) to that of glucose during the first 30 min of the OGTT (delta IRI[30 min-0 min]/delta glucose[30 min-0 min]) performed at baseline and at 5 years of follow-up. Beta-cell function adjusted for basal IRI ([delta IRI[30 min-0 min]/delta glucose[30 min-0 min]]/basal IRI; the relative insulin response) was also evaluated. At baseline, the -30 beta-cell GCK gene promoter variant was present in 15.4% of subjects with NGT vs. 38.3% of subjects with IGT (P < 0.01). Fasting IRI did not differ between groups. At baseline, delta IRI[30 min-0 min]/delta glucose[30 min-0 min] was significantly lower in subjects with the promoter variant (57 x 10(-9) [35 x 10(-9) to 95 x 10(-9)] vs. 77 x 10(-9) [55 x 10(-9) to 128 x 10(-9)]; median [interquartile range]; P < 0.01) as was the relative insulin response (0.97 [0.70-1.24] vs. 1.37 [0.95-2.03]l/mmol; P < 0.0005). Similarly, at 5 years of follow-up, delta IRI[30 min-0 min]/delta glucose[30 min-0 min] and the relative insulin response were significantly reduced in the group with the variant. In the subgroups of subjects with IGT at baseline, IGT at 5 years, and NGT at 5 years, the relative insulin response was significantly lower in those with the variant. We conclude that the -30 beta-cell GCK gene promoter variant is associated with reduced beta-cell function in middle-aged Japanese-American men and may contribute to the high risk of abnormal glucose tolerance in this population.

Aged↗
PubMed1996

The GENNID Study. A resource for mapping the genes that cause NIDDM.

OBJECTIVE: To develop a resource, consisting of comprehensive data and lymphoblastoid cell lines, of well-characterized NIDDM families that will be available to the scientific community for genetic studies of NIDDM. RESEARCH DESIGN AND METHODS: Non-Hispanic white, Hispanic, African-American, and Japanese-American multiplex NIDDM families, with a minimum of one affected sib-pair, are being collected by the eight Harold Rifkin Family Acquisition Centers. Detailed family and medical histories are obtained from all participants. Family members with diabetes have fasting blood samples drawn, while nondiabetic family members have an oral glucose tolerance test and, when possible, insulin sensitivity and insulin secretion measurements by frequently sampled intravenous glucose tolerance testing or euglycemic insulin clamp. Lymphoblastoid cell lines are established for all participants. RESULTS: Over 1,400 individuals from approximately 220 families have been studied since the start of the GENNID (Genetics of NIDDM) program in July 1993. The goal is that by July 1997, data from 300 non-Hispanic white families, > 100 Hispanic families, > 100 African-American families, and 15 Japanese-American families will have been collected. CONCLUSIONS: The identification of the genes responsible for NIDDM may now be achievable, but only if sound phenotypic data are linked to genetic material from a large number of well-described multiplex families. The GENNID project of the American Diabetes Association is creating a comprehensive resource that will expedite the identification of the genetic basis of NIDDM.

Black or African American↗
PubMed1996

Proinsulin levels predict the development of non-insulin-dependent diabetes mellitus (NIDDM) in Japanese-American men.

Disproportionate hyperproinsulinaemia is a manifestation of the beta-cell dysfunction observed in NIDDM. However, it is unclear when this abnormality develops and whether it predicts the development of the disease. To examine whether changes in proinsulin levels predict the development of NIDDM, baseline measurements of proinsulin and immunoreactive insulin levels were made in 87 second-generation Japanese-American men, a population at high risk for the subsequent development of NIDDM. Subjects were categorized at baseline using WHO criteria as having normal glucose tolerance (NGT; n = 49) or impaired glucose tolerance (IGT; n = 38). After a 5-year follow-up period, subjects were recategorized as having NGT, IGT or NIDDM using the same criteria. During follow-up, 16 subjects developed NIDDM while 71 were NGT or IGT. At baseline, individuals who subsequently developed NIDDM were more obese as measured by intra-abdominal fat area on computed tomography (p = 0.046), had higher fasting glucose (p = 0.0042), 2-h glucose (p = 0.0002), fasting C-peptide (p = 0.0011), fasting proinsulin levels (p = 0.0033), and had disproportionate hyperproinsulinaemia (p = 0.056) when compared to those who remained NGT or IGT after 5 years of follow-up. These findings suggest that alterations in proinsulin levels may also predict the subsequent development of NIDDM.

Asian↗
PubMed1995

Changes in insulin sensitivity, glucose effectiveness, and B-cell function in regularly exercising subjects.

To determine the relative contributions of changes in glucose effectiveness, B-cell function, and insulin sensitivity to changes in glucose tolerance upon exercise cessation in regularly exercising individuals, we studied seven young subjects who were performing aerobic exercise on a regular schedule. Each subject was studied 12 and 84 hours after the last bout of exercise with an intravenous glucose tolerance test (IVGTT) to quantify insulin sensitivity and glucose effectiveness at zero insulin (GEZI) using the minimal model of glucose kinetics. Additionally, B-cell function was quantified as the acute insulin response to glucose (AIRglucose), and intravenous glucose tolerance as the glucose disappearance constant (Kg). Twelve hours after the last bout of exercise, SI was 8.47 +/- 1.12 x 10(-5) min-1/pmol/L, as compared with 6.98 +/- 1.17 x 10(-5) min-1/pmol/L 84 hours after exercise (mean +/- SE, P = .005). No changes was observed in GEZI (0.020 +/- 0.004 min-1 at 12 hours v 0.019 +/- 0.002 min-1 at 84 hours, P = NS) or AIRglucose (588 +/- 213 pmol/L at 12 hours v 687 +/- 271 pmol/L at 84 hours, P = NS). Thus, the difference in intravenous glucose tolerance observed 12 hours after exercise as compared with 84 hours after the last bout of exercise (Kg, 2.91 +/- 0.70%/min at 12 hours v 2.23 +/- 0.60%/min at 84 hours, P < .05) would appear to be entirely related to a difference in SI and not to differences in glucose effectiveness or B-cell function.

Adult↗
PubMed1995

Relationship of proinsulin and insulin with noninsulin-dependent diabetes mellitus and coronary heart disease in Japanese-American men: impact of obesity--clinical research center study.

Obesity is associated with noninsulin-dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD), and these interactions have usually been related to changes in immunoreactive insulin (IRI) levels. A role of proinsulin (PI) in this association has been suggested. We, therefore, examined IRI, PI, and true insulin levels and the PI/IRI ratio by glucose tolerance or CHD status in a cross-sectional study of 170 Japanese-American men (45-74 yr old) in whom 2 measures of adiposity (body mass index and intraabdominal fat) were made to assess potential associations in this population with a high prevalence of both NIDDM and CHD. Subjects were classified as having normal glucose tolerance (n = 58), impaired glucose tolerance (IGT; n = 55), or NIDDM (n = 57) or were classified by CHD status (without CHD, n = 127; with CHD, n = 43). A positive linear relationship existed between obesity, determined either as the body mass index or intraabdominal fat, and IRI, PI, and true insulin, but not the PI/IRI ratio. In the NIDDM subjects, PI levels were disproportionately greater than those in subjects with normal glucose tolerance or IGT, so the PI/IRI ratio was significantly greater in the NIDDM group [mean (95% confidence interval): normal glucose tolerance, 11.8% (range, 10.4-13.5); IGT, 12.8% (range, 10.8-15.1); NIDDM, 19.2% (range, 15.4-24.0); P = 0.0002] even when adjusted for obesity (P = 0.0004). In subjects with CHD compared to subjects without CHD, IRI (P = 0.0026) and true insulin levels (P = 0.0043) were increased, but PI levels were not. However, these differences were not present after adjustment for obesity. In contrast, when intraabdominal fat was adjusted for IRI or true insulin, a significant effect of intraabdominal fat on CHD risk was maintained (P = 0.045 and P = 0.029, respectively), suggesting that another factor(s) associated with central obesity may be involved in CHD risk. Thus, in Japanese-American men, elevated PI and PI/IRI ratio are markers of B-cell dysfunction, and these are not the result of obesity. An elevated true insulin level is present in those with CHD, but this appears to be the result of obesity. In contrast, central adiposity confers an additional risk for CHD independent of insulin.

Adipose Tissue↗
PubMed1995

Reduced insulin secretion: an independent predictor of body weight gain.

A causal role in the pathogenesis of obesity has been proposed for hyperinsulinemia and insulin resistance in populations with a high prevalence of a "thrifty genotype." An alternative hypothesis is that obesity-induced hyperinsulinemia is an adaptation which, by increasing central nervous system insulin signaling (which suppresses food intake), confers resistance to weight gain. To characterize the relationship between the level of insulin secretion and the risk of weight gain, we examined whether any of three different measures of the level of insulin secretion (the area under the plasma insulin curve during both a meal tolerance test and an oral glucose tolerance test, and the acute insulin secretory response to iv glucose) was predictive of weight gain in a prospective study of 97 Pima Indians (64 males and 33 females) with normal glucose tolerance. During a mean (+/- SD) follow-up period of more than 3 yr (males, 3.58 +/- 1.46 yr; females, 3.02 +/- 1.73 yr), average weight increased 2.1 +/- 3.0%/yr in males and 3.5 +/- 3.6%/yr in females, reflecting a mean annual increase in body fat content of 6.9%/yr in both sexes. Insulin secretion was negatively associated with the rate of weight gain, whether assessed by the insulin response during the meal tolerance test (r = -0.35; P < 0.001), the oral glucose tolerance test (r = -0.30; P = 0.004), or the acute insulin secretory response to iv glucose (r = -0.28; P = 0.002). Moreover, the significance of the relationship between each measure of insulin secretion and weight gain persisted after controlling for differences in age, sex, initial body weight, and insulin sensitivity. Relatively reduced insulin secretion, therefore, is a significant and independent predictor of the tendency to gain weight and adiposity in Pima Indians. The presence of relative insulin resistance also conferred an independent reduction in the risk of weight gain in some regression analyses. We conclude that insulin resistance and hyperinsulinemia are unlikely to play a causal role in the development of obesity, and that relatively reduced insulin secretion is a marker of an increased risk of weight gain in this population. These conclusions support the hypothesis that the level of insulin secretion plays an important role in long term body weight regulation.

Adipose Tissue↗
PubMed1995

Proinsulin as a marker for the development of NIDDM in Japanese-American men.

Disproportionate hyperproinsulinemia is one manifestation of the B-cell dysfunction observed in non-insulin-dependent diabetes mellitus (NIDDM), but it is unclear when this abnormality develops and whether it predicts the development of NIDDM. At baseline, measurements of proinsulin (PI) and immunoreactive insulin (IRI) levels were made in 87 second-generation Japanese-American men, a population at high risk for the subsequent development of NIDDM, and, by using World Health Organization criteria, subjects were categorized as having normal glucose tolerance (NGT; n = 49) or impaired glucose tolerance (IGT; n = 38). After a 5-year follow-up period, they were recategorized as NGT, IGT, or NIDDM using the same criteria. After 5 years, 16 subjects had developed NIDDM, while 71 had NGT or IGT. Individuals who developed NIDDM were more obese at baseline, measured as intra-abdominal fat (IAF) area on computed tomography (P = 0.046) but did not differ in age from those who continued to have NGT or IGT. At baseline, subjects who subsequently developed NIDDM had higher fasting glucose (P = 0.0042), 2-h glucose (P = 0.0002), fasting C-peptide (P = 0.0011), and fasting PI levels (P = 0.0033) and disproportionate hyperproinsulinemia (P = 0.056) than those who continued to have NGT or IGT after 5 years of follow-up. NIDDM incidence was positively correlated with the absolute fasting PI level (relative odds = 2.35; P = 0.0025), even after adjustment for fasting IRI, IAF, and body mass index (relative odds = 2.17; P = 0.013).(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen↗
PubMed1995

The key role of islet dysfunction in type II diabetes mellitus.

Fasting plasma glucose levels are constant from day to day in normal individuals. This constancy is due to a close co-ordination between glucose production by the liver and glucose uptake in peripheral tissues. This review focusses on the key role of the endocrine pancreas alpha- and beta-cells to provide this co-ordination. Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by fasting hyperglycemia. The degree of fasting hyperglycemia, in turn, is correlated with the basal rate of hepatic glucose production. This increased rate of glucose release by the liver results in part from impaired hepatic sensitivity to insulin, but is largely due to reduced insulin secretion and increased glucagon secretion. Though basal immunoreactive insulin and glucagon levels in patients with NIDDM may appear normal when compared to those of healthy individuals, islet function testing at matched glucose levels reveals impairments of basal, steady-state, and stimulated insulin and glucagon secretion due to a reduction in beta-cell secretory capacity and a reduced ability of glucose to suppress glucagon release. The degree of impaired beta-cell responsiveness to glucose is closely related to the degree of fasting hyperglycemia, but in a curvilinear fashion. Thus, islet alpha- and beta-cell function is reduced by more than 50% in NIDDM by the time that clinical fasting hyperglycemia develops (140 mg/dL). 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes Mellitus, Type 2↗
PubMed1994

The visceral adiposity syndrome in Japanese-American men.

Japanese-Americans have an increased prevalence of non-insulin-dependent diabetes mellitus and coronary heart disease when compared to native Japanese. This increase has been associated with fasting hyperinsulinemia, hypertriglyceridemia, and low plasma levels of high-density lipoprotein (HDL) cholesterol. The purpose of this study was to examine the relationship of both visceral adiposity and insulin resistance to this metabolic syndrome and to the presence of a predominance of small, dense low-density lipoprotein (LDL) particles (LDL subclass phenotype B) that has been associated with increased atherogenic risk. Six Japanese-American men with non-insulin-dependent diabetes, each receiving an oral sulfonylurea, were selected. One or 2 nondiabetic Japanese-American men, matched by age and body mass index, were selected for each diabetic subject, giving a total of 9 nondiabetic men. Diabetic subjects had significantly higher fasting plasma glucose (p=0.0007) and lower insulin sensitivity (SI, p=0.018) using the minimal model technique than nondiabetic subjects matched for body mass index. Six men (2 with diabetes) had LDL phenotype A and 8 (4 with diabetes) had phenotype B. One nondiabetic subject had an intermediate low-density lipoprotein pattern. Significantly greater amounts of intra-abdominal fat (p=0.045) measured by computed tomography were found in the men with phenotype B while fasting insulin (p=0.070) and triglycerides (p=0.051) tended to be higher. free fatty acids (r=0.677), LDL density (relative flotation rate, r=-0.803), and plasma HDL-cholesterol (r=-0.717). SI was significantly correlated only with plasma free fatty acids (r=-0.546) and tended to be correlated with hepatic lipase activity (r=-0.512, p=0.061). In conclusion, these observations indicate that in non-obese Japanese-American men, the metabolic features of the so-called insulin resistance syndrome, including LDL phenotype B, are more strongly correlated with visceral adiposity than with SI. It may therefore be more appropriate to call this the visceral adiposity syndrome. Although questions concerning mechanisms still remain, we postulate that visceral adiposity plays a central role in the development of many of the metabolic abnormalities, including LDL subclass phenotype B, that occur in this metabolic syndrome.

Abdomen↗
PubMed1994

Transgenic mice overproducing islet amyloid polypeptide have increased insulin storage and secretion in vitro.

To determine whether chronic overproduction of islet amyloid polypeptide alters beta-cell function, we studied a line of transgenic mice which overexpress islet amyloid polypeptide in their beta-cells. At 3 months of age, these transgenic mice had greater pancreatic content of both islet amyloid polypeptide and insulin. Further, basal and glucose-stimulated secretion of both islet amyloid polypeptide and insulin were also elevated in the perfused pancreas of the transgenic animals. These findings demonstrate that chronic overproduction and secretion of islet amyloid polypeptide are associated with increased insulin storage and enhanced secretion of insulin in vitro. This increase in insulin storage and secretion may be due to a direct effect of islet amyloid polypeptide on the beta-cell or a beta-cell adaptation to islet amyloid polypeptide-induced insulin resistance.

Amyloid↗
PubMed1994

Reliability of error estimates from the minimal model: implications for measurements in physiological studies.

MINMOD provides an estimate of the error in the insulin sensitivity index (SI) and glucose effectiveness at basal insulin (Sg) as the fractional standard deviation (FSD). The validity of the FSD estimate has not been assessed in a large number of human studies, nor has a comparison of the accuracies achievable using the two different intravenous glucose tolerance test (IVGTT) protocols (glucose only and tolbutamide protocol) been performed. To address these two issues, we obtained the FSD value and performed Monte Carlo simulations for 237 IVGTT studies. The FSD underestimated the true error as determined as the coefficient of variation from Monte Carlo simulation (COV-MC) with the ratio of COV-MC to FSD being 3.07 +/- 0.20 (mean +/- SE) for SI using the tolbutamide protocol. Additionally, the mean COV-MC for glucose-only protocol was approximately two to three times that for the tolbutamide protocol for both SI and Sg. We conclude that FSD underestimates the true error in SI and Sg. Additionally, more accurate results are obtained from the tolbutamide protocol than with the glucose-only protocol.

Computer Simulation↗
PubMed1994

Glucagon-like peptide 1 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin-independent glucose disposal.

Glucagon-like peptide 1 [7-36 amide] (GLP-1) has been shown to enhance insulin secretion in healthy and type II diabetic humans, and to increase glucose disposal in type I diabetic patients. To further define its action on glucose kinetics, we studied six healthy subjects who received either GLP-1 (45 pmol/kg per h) or 150 mM saline on two mornings during which a modified intravenous glucose tolerance test was performed. Plasma insulin and glucose levels were analyzed using Bergman's minimal model of glucose kinetics to derive indices of insulin sensitivity (SI) and glucose effectiveness at basal insulin (SG), the latter a measure of glucose disposition independent of changes in insulin. In addition, basal insulin concentrations, the acute insulin response to glucose (AIRg), plasma glucagon levels, and the glucose disappearance constant (Kg) were measured on the days that subjects received GLP-1 or saline. Compared with saline infusions, GLP-1 increased the mean Kg from 1.61 +/- 0.20 to 2.65 +/- 0.25%/min (P = 0.022). The enhanced glucose disappearance seen with GLP-1 was in part the result of its insulinotropic effect, as indicated by a rise in AIRg from 240 +/- 48 to 400 +/- 78 pM (P = 0.013). However, there was also an increase in SG from 1.77 +/- 0.11 to 2.65 +/- 0.33 x 10(-2).min-1 (P = 0.038), which was accounted for primarily by insulin-independent processes, viz glucose effectiveness in the absence of insulin. There was no significant effect of GLP-1 on SI or basal insulin, and glucagon levels were not different during the glucose tolerance tests with or without GLP-1. Thus, GLP-1 improves glucose tolerance both through its insulinotropic action and by increasing glucose effectiveness. These findings suggest that GLP-1 has direct effects on tissues involved in glucose disposition. Furthermore, this peptide may be useful for studying the process of insulin-independent glucose disposal, and pharmacologic analogues may be beneficial for treating patients with diabetes mellitus.

Adult↗
PubMed1994

Pancreatic expression and secretion of human islet amyloid polypeptide in a transgenic mouse.

Islet amyloid polypeptide (IAPP) is a secretory product of the pancreatic beta-cell, which is the primary constituent of the islet amyloid that develops in type II diabetes. To study the role the inherent amyloidogenicity of human IAPP (hIAPP) plays in the formation of islet amyloid deposits and to investigate a possible hormonal role for IAPP, transgenic mice expressing hIAPP were developed. The transgene was composed of a fragment of an hIAPP cDNA linked to the rat insulin II promoter. One line of transgenic mice expressed the transgene and synthesized hIAPP in their pancreatic islets. IAPP-like immunoreactivity in pancreatic extracts and plasma were two- to threefold greater in the transgenic mice compared with nontransgenic control mice. Although plasma concentrations of immunoreactive insulin (IRI) and glucose were equal in transgenic and control mice, the pancreatic content of IRI was nearly twofold greater in the transgenic animals, and proinsulin mRNA was significantly elevated, suggesting increased rates of insulin biosynthesis. Pancreatic samples obtained from transgenic mice up to 19 months of age had no evidence of islet amyloid. These results indicate that an increased level of synthesis of the amyloidogenic hIAPP is not sufficient to cause islet amyloid deposition. However, the increased synthesis and storage of insulin in the islets of the transgenic mice are consistent with either a direct regulatory effect of IAPP on the beta-cell or indirect stimulation of insulin production through IAPP-induced insulin resistance.

Amyloid↗
PubMed1994

The contribution of insulin-dependent and insulin-independent glucose uptake to intravenous glucose tolerance in healthy human subjects.

Glucose disposal occurs by both insulin-independent and insulin-dependent mechanisms, the latter being determined by the interaction of insulin sensitivity and insulin secretion. To determine the role of insulin-independent and insulin-dependent factors in glucose tolerance, we performed intravenous glucose tolerance tests on 93 young healthy subjects (55 male, 38 female; 18-44 years of age; body mass index, 19.5-52.2 kg/m2). From these tests, we determined glucose tolerance as the glucose disappearance constant (Kg), calculated beta-cell function as the incremental insulin response to glucose for 19 min after an intravenous glucose bolus (IIR0-19), and derived an insulin sensitivity index (SI) and glucose effectiveness at basal insulin (SG) using the minimal model of glucose kinetics. To eliminate the effect of basal insulin on SG and estimate insulin-independent glucose uptake, we calculated glucose effectiveness at zero insulin (GEZI = SG - [SI x basal insulin]). Insulin-dependent glucose uptake was estimated as SI x IIR0-19, because the relationship between SI and beta-cell function has been shown to be hyperbolic. Using linear regression to determine the influence of these factors on glucose tolerance, we found that GEZI was significantly related to Kg (r = 0.70; P < 0.0001), suggesting a major contribution of insulin-independent glucose uptake to glucose disappearance. As expected, SI x IIR0-19 also correlated well with Kg (r = 0.74; P < 0.0001), confirming the importance of insulin-dependent glucose uptake to glucose tolerance. Although IIR0-19 alone correlated with Kg (r = 0.35; P = 0.0005), SI did not (r = 0.18; P > 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Glucokinase gene variations in Japanese-Americans with a family history of NIDDM.

OBJECTIVE: To determine if sequence variants in the glucokinase (GCK) gene contribute to the high risk of impaired glucose metabolism in Japanese-Americans and whether the gene sequence differs between Japanese-Americans and Caucasians. RESEARCH DESIGN AND METHODS: Forty-seven unrelated Japanese-Americans with one or more first-degree relatives with non-insulin-dependent diabetes mellitus (NIDDM) were selected, irrespective of glucose tolerance status. By World Health Organization criteria, 13 had normal glucose tolerance, 11 had impaired glucose tolerance, and 23 had NIDDM. Variations in the GCK gene were identified by single-strand conformation polymorphism analysis and sequenced using standard techniques. RESULTS: Six variants of the GCK gene were identified in a total of 21 subjects: 1) a G--> A substitution at nucleotide -30 in the beta-cell-specific promoter; 2) an A--> G substitution at nucleotide 244 in the 5'-untranslated region (5'-UTR) of exon 1a; 3) a C--> G substitution at nucleotide 403 in the 5'-UTR of exon 1a; 4) a G--> A variant 13 base pair (bp) 5' to the intron 3 exon 4 junction; 5) a silent substitution in the third base of codon 145 in exon 4; and 6) a C--> T substitution 8 bp 3' to the exon 9 intron 9 junction. None of these variations would be expected to affect the structure of the GCK enzyme. While none of these variants were significantly associated with IGT or NIDDM, a nonsignificant increase in the beta-cell promoter variant was observed in subjects with abnormal glucose tolerance. No uniform sequence differences in the GCK gene were identified between Japanese-American and Caucasian-American subjects. CONCLUSIONS: Mutations affecting the amino acid sequence of GCK do not account for the increased incidence of impaired glucose metabolism in Japanese-Americans, and the gene sequence does not uniformly differ from that in Caucasians.

Adult↗