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S E Kahn

Publications and source records attributed to S E Kahn.

At least 37 records · Page 2Linked to original sources
PubMed2001

beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms.

Type 2 diabetes is characterized by a progressive loss of beta-cell function throughout the course of the disease. The pattern of loss is an initial defect in early or first-phase insulin secretion, followed by a decreasing maximal capacity of glucose to potentiate all nonglucose signals. Last, a defective steady-state and basal insulin secretion develops, leading to complete beta-cell failure requiring insulin treatment. This functional loss exceeds the expected impact of a 20-50% loss of beta-cells reported at autopsy, which has been associated with amyloid deposits. This review summarizes the nature of the amyloid deposition process and its association with disproportionate hyperproinsulinemia. It reviews recent studies in IAPP (islet-amyloid polypeptide, or amylin) transgenic mice developing islet amyloid deposits and hyperglycemia to suggest that the process of amyloid fibril formation impairs function early and leads to beta-cell failure and eventual death. Based on the known association of amyloid deposits and relative hyperproinsulinemia, it is hypothesized that fibril formation begins during impaired glucose tolerance after other factors cause the initial defects in early insulin secretion and insulin action. Thus, the process that leads to beta-cell loss is implicated in the deposition of amyloid and the late unrelenting progressive hyperglycemia now found in all patients despite current therapies.

Amyloid↗
PubMed2001

Abnormal glucose tolerance and increased risk for cardiovascular disease in Japanese-Americans with normal fasting glucose.

OBJECTIVE: To compare the American Diabetes Association (ADA) fasting glucose and the World Health Organization (WHO) oral glucose tolerance test (OGTT) criteria for diagnosing diabetes and detecting people at increased risk for cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: Study subjects were 596 Japanese-Americans. Fasting insulin, lipids, and C-peptide levels; systolic and diastolic blood pressures (BPs); BMI (kg/m2); and total and intra-abdominal body fat distribution by computed tomography (CT) were measured. Study subjects were categorized by ADA criteria as having normal fasting glucose (NFG), impaired fasting glucose (IFG), and diabetic fasting glucose and by WHO criteria for a 75-g OGTT as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetic glucose tolerance (DGT). RESULTS: Of 503 patients with NFG, 176 had IGT and 20 had DGT These patients had worse CVD risk factors than those with NGT . The mean values for NGT, IGT, and DGT, respectively, and analysis of covariance P values, adjusted for age and sex, are as follows; intra-abdominal fat area by CT 69.7, 95.0, and 101.1 cm2 (P < 0.0001); total CT fat area 437.7, 523.3, and 489.8 cm2 (P < 0.0001); fasting triglycerides 1.40, 1.77, and 1.74 mmol/l (P = 0.002); fasting HDL cholesterol 1.56, 1.50, and 1.49 mmol/l (P = 0.02); C-peptide 0.80, 0.90, 0.95 nmol/l (P = 0.002); systolic BP 124.9, 132.4, and 136.9 mmHg (P = 0.0035); diastolic BP 74.8, 77.7, and 78.2 mmHg (P = 0.01). CONCLUSIONS: NFG patients who had IGT or DGT had more intra-abdominal fat and total adiposity; higher insulin, C-peptide, and triglyceride levels; lower HDL cholesterol levels; and higher BPs than those with NGT. Classification by fasting glucose misses many Japanese-Americans with abnormal glucose tolerance and less favorable cardiovascular risk profiles.

Adult↗
PubMed2001

Standardization of cardiac troponin I assays: round Robin of ten candidate reference materials.

BACKGROUND: Cardiac troponin I (cTnI) results vary 100-fold among assays. As a step toward standardization, we examined the performance of 10 candidate reference materials (cRMs) in dilution studies with 13 cTnI measurement systems. METHODS: Solutions of 10 cTnI cRMs, each characterized by NIST, were shipped to the manufacturers of 13 cTnI measurement systems. Manufacturers used their respective diluents to prepare each cRM in cTnI concentrations of 1, 10, 25, and 50 microg/L. For the purpose of ranking the cRMs, the deviation of each cTnI measurement from the expected response was assessed after normalization with the 10 microg/L cTnI solution. Normalized deviations were examined in five formats. Parameters from linear regression analysis of the measured cTnI vs expected values were also used to rank performance of the cRMs. RESULTS: The three cRMs demonstrating the best overall rankings were complexes of troponins C, I, and T. The matrices for these three cRMs values differed; one was reconstituted directly from the lyophilized form submitted by the supplier; one was submitted in liquid form, lyophilized at NIST, and subsequently reconstituted; and the third was evaluated in the liquid form received from the supplier. The cRM demonstrating the fourth best performance was a binary complex of troponins C and I supplied in lyophilized form and reconstituted before distribution. CONCLUSIONS: The cRMs demonstrating the best performance characteristics in 13 cTnI analytical systems will be included in subsequent activities of the cTnI Standardization Committee of the AACC.

Algorithms↗
PubMed2001

Beta cell failure: causes and consequences.

In recent years a great deal of discussion has focused on the relative roles of insulin resistance and beta-cell dysfunction in the pathogenesis of type 2 diabetes. When considering their relative importance it is critical that the two variables are considered in concert. Alterations in insulin secretion are present in patients with type 2 diabetes and can be demonstrated in high risk individuals well before diagnosis. Loss of the early phase of insulin secretion can be demonstrated following oral or intravenous glucose administration. The relationship of early insulin secretion to insulin sensitivity in normal individuals is represented by a hyperbolic curve in keeping with the existence of a feedback loop. Deviations from standardised curves demonstrate defects in both insulin secretion and sensitivity in individuals who are at risk of developing diabetes. The reduction in the early phase insulin response results in impaired suppression of hepatic glucose production. Glucose output by the liver is not inversely proportionate to glucose influx, resulting in postprandial hyperglycaemia. Therapeutic approaches must address defects in both the early insulin response and insulin sensitivity. New oral agents that stimulate early insulin secretion and rapid-acting insulin analogues are targeting this early insulin secretion defect.

Diabetes Mellitus, Type 2↗
PubMed2000

The importance of the beta-cell in the pathogenesis of type 2 diabetes mellitus.

beta-cell dysfunction and insulin resistance are two central, interrelated defects in the pathophysiology of type 2 diabetes. By the time a patient's hyperglycemia is recognized, disruption of the normal relationship between beta-cell function and insulin sensitivity is already well established. The pathophysiology and progression of defects in glucose metabolism from normal glucose tolerance to impaired glucose tolerance to frank type 2 diabetes have been studied extensively. Insulin sensitivity has wide intersubject variability, and many individuals at risk for type 2 diabetes are insulin resistant. beta-cell changes in patients with type 2 diabetes include defects in insulin secretion, proinsulin conversion to insulin, and amyloid deposition in the islet. Studies in several ethnic groups have established that the progression from normal glucose tolerance to frank type 2 diabetes results from a gradual deterioration in beta-cell function in the presence of insulin resistance. Furthermore, the recently completed landmark United Kingdom Prospective Diabetes Study demonstrated that type 2 diabetes is a progressive disease and that this progression is due to declining beta-cell function.

Diabetes Mellitus, Type 2↗
PubMed2000

Oophorectomy promotes islet amyloid formation in a transgenic mouse model of Type II diabetes.

AIMS/HYPOTHESIS: In Type II (non-insulin-dependent) diabetes mellitus, amyloid depletes islet mass. We previously found that 81% of male human islet amyloid polypeptide (IAPP) transgenic mice but only 11% of female mice developed islet amyloid, suggesting that either testosterone promotes or ovarian products protect against amyloid deposition. METHODS: We did a bilateral oophorectomy or sham procedure in female human IAPP transgenic mice (n = 11 and n = 8, respectively) and in female non-transgenic mice (n = 7 and n = 9, respectively) at 6-8 weeks of age. Animals were followed for 1 year on a 9% fat (w/w) diet. Before we killed them we measured, fasting plasma human IAPP and did an intraperitoneal glucose tolerance test. Pancreatic content of IAPP and immunoreactive insulin (IRI) were estimated and pancreata were analysed for islet amyloid. RESULTS: No amyloid was detected in either the sham-operated transgenic mice or, as expected, in both groups of non-transgenic mice. In strong contrast, 7 of 11 (64%) oophorectomized mice developed islet amyloid (p < 0.05). Amyloid deposition in the oophorectomized transgenic mice was not associated with any differences in incremental body weight, fasting human IAPP concentrations or glucose tolerance between the groups. Furthermore, pancreatic content of mouse IAPP, human IAPP and immunoreactive insulin did not differ between groups. CONCLUSION/INTERPRETATION: Oophorectomy is associated with an enhancement of islet amyloid formation in the absence of changes in glucose tolerance, circulating IAPP or pancreatic content of IRI, mouse or human IAPP. Thus, the early stages of islet amyloidogenesis seem to be independent of glucose tolerance, with ovarian products having a protective role.

Amyloid↗
PubMed2000

Type 2 diabetes and the metabolic syndrome in Japanese Americans.

Japanese Americans have experienced a higher prevalence of type 2 diabetes than in Japan. Research conducted in Seattle suggests that lifestyle factors associated with 'westernization' play a role in bringing out this susceptibility to diabetes. These lifestyle factors include consumption of a diet higher in saturated fat and reduced physical activity. A consequence of this is the development of central (visceral) adiposity, insulin resistance, and other features associated with this insulin resistance metabolic syndrome, such as dyslipidemia (high triglycerides, low HDL-cholesterol, and small and dense LDL particles), hypertension, and coronary heart disease. We have postulated that the superimposition of insulin resistance upon a genetic background of reduced beta-cell reserve results in hyperglycemia and diabetes among Japanese Americans. This article reviews evidence that support this view.

Adipose Tissue↗
PubMed2000

Preventing diabetes--applying pathophysiological and epidemiological evidence.

This is a review of research carried out in Japanese Americans that points towards possible approaches to prevention of type 2 diabetes mellitus. The natural history of type 2 diabetes usually includes both insulin resistance and beta-cell dysfunction. Insulin secretion may compensate for insulin resistance. Alternatively, enhanced insulin sensitivity may mask an insulin secretory defect. Epidemiological data support the view that in the vast majority of cases of type 2 diabetes, insulin resistance is essential to the pathogenesis of hyperglycemia. Increased diabetes prevalence as ethnic groups migrate to more urban or westernized regions has been attributed to increased occurrence of insulin resistance. Research among Japanese Americans in Seattle, Washington, showed a higher prevalence of type 2 diabetes than in Japan, which suggested that factors associated with 'westernization' might be playing a role in bringing out underlying susceptibility to diabetes. Our research has shown that these impressions were correct and that the abnormalities that characterize the metabolic syndrome play a significant role. Due to increased intra-abdominal fat deposition, Japanese Americans were likely to be 'metabolically obese' despite relatively normal BMI. A diet higher in animal fat and lower levels of physical activity were risk factors leading to increased intra-abdominal fat deposition, insulin resistance, and diabetes. Information from epidemiological studies such as these may be used to determine whether diabetes may be prevented through changes in lifestyle or application of specific therapies targeted towards identified metabolic abnormalities.

Adult↗
PubMed2000

Effect of weight loss with reduction of intra-abdominal fat on lipid metabolism in older men.

How weight loss improves lipid levels is poorly understood. Cross-sectional studies have suggested that accumulation of fat in intra-abdominal stores (IAF) may lead to abnormal lipid levels, increased hepatic lipase (HL) activity, and smaller low density lipoprotein (LDL) particle size. To determine what effect loss of IAF would have on lipid parameters, 21 healthy older men underwent diet-induced weight loss. During a period of weight stability before and after weight loss, subjects underwent studies of body composition, lipids, measurement of postheparin lipoprotein and HL lipase activities, cholesteryl ester transfer protein activity, and insulin sensitivity (Si). After an average weight loss of 10%, reductions in fat mass, IAF, and abdominal s.c. fat were seen, accompanied by reductions in levels of triglyceride, very low density lipoprotein cholesterol, apolipoprotein B, and HL activity. High density lipoprotein-2 cholesterol and Si increased. In those subjects with pattern B LDL at baseline, LDL particle size increased. Cholesteryl ester transfer protein activity did not change. Changes in IAF and Si correlated with a decrease in HL activity (although not independently of each other). In summary, in men undergoing diet-induced weight loss, only loss of IAF was found to be associated with a reduction in HL, which is associated with beneficial effects on lipid levels.

Abdomen↗
PubMed2000

Reduced pancreatic B cell compensation to the insulin resistance of aging: impact on proinsulin and insulin levels.

Type 2 diabetes mellitus is associated with insulin resistance, reduced B cell function, and an increase in the proinsulin (PI) to immunoreactive insulin (IRI) ratio (PI/IRI); the latter is thought to be an indication of B cell dysfunction. Normal aging is associated with insulin resistance and reduced B cell function, but it is not known whether changes in PI and the PI/IRI ratio are also a feature of the aging-associated B cell dysfunction. Therefore, we tested whether the aging-associated changes in insulin sensitivity and B cell function result in changes in PI and IRI levels that are proportionate or whether they are disproportionate as in type 2 diabetes. Twenty-six healthy older (mean +/- SEM age, 67 +/- 1 yr) and 22 younger (28 +/- 1 yr) subjects with similar body mass indexes (27.9 +/- 0.6 vs. 26.3 +/- 1.0 kg/m2) were studied. PI was measured by a RIA recognizing both intact PI and its conversion intermediates. The insulin sensitivity index (SI) was quantified using the minimal model, and B cell function was measured as fasting insulin levels, the acute insulin response to glucose (AIRglucose), and as the acute insulin response to arginine at maximal glycemic potentiation (AIRmax). B cell function was also adjusted for SI based on the known hyperbolic relationship between these two variables. Older and younger subjects had similar fasting glucose (5.3 +/- 0.1 vs. 5.2 +/- 0.1 mmol/L), IRI (83 +/- 8 vs. 76 +/- 9 pmol/L), PI (8.9 +/- 0.8 vs. 10.6 +/- 2.0 pmol/L), and PI/IRI ratio (12.3 +/- 1.3% vs. 13.9 +/- 1.6%; all P = NS) despite a 50% reduction of insulin sensitivity (SI, 1.94 +/- 0.21 vs. 3.88 +/- 0.38 x 10(-5) min(-1)/pmol x L; P < 0.001) and in B cell function [SI x fasting IRI, 139 +/- 18 vs. 244 +/- 24 x 10(-5)(P < 0.001); SI x AIRglucose, 0.75 +/- 0.13 vs. 1.70 +/- 0.15 x 10(-2) min(-1) (P < 0.001); SI x AIRmax, 3.63 +/- 0.53 vs. 6.81 +/- 0.70 x 10(-2) min(-1) (P < 0.001)] in the older subjects. These findings suggest that the B cell dysfunction in older subjects is not associated with disproportionate proinsulinemia. However, in older subjects the B cell response to the insulin resistance of aging is reduced whether measured as fasting levels of PI or IRI or as the acute response to secretagogues. Thus, when examined in terms of the degree of insulin sensitivity, the lower fasting IRI levels in older subjects suggest that the utility of fasting insulin levels as a surrogate measure of insulin resistance in older individuals may be limited.

Adult↗
PubMed2000

beta-cell glucokinase deficiency and hyperglycemia are associated with reduced islet amyloid deposition in a mouse model of type 2 diabetes.

Type 2 diabetes is characterized by impaired beta-cell function, hyperglycemia, and islet amyloid deposition. The primary constituent of islet amyloid is the 37-amino acid beta-cell product called islet amyloid polypeptide (IAPP) or amylin. To study mechanisms of islet amyloid formation, we developed a transgenic mouse model that produces and secretes the amyloidogenic human IAPP (hIAPP) molecule and have shown that 81% of male transgenic mice develop islet amyloid after 14 months on a high-fat diet. To test whether impaired beta-cell function and hyperglycemia could enhance islet amyloid formation, we cross-bred our hIAPP transgenic mice with beta-cell glucokinase-knockout mice (GKKO) that have impaired glucose-mediated insulin secretion and fasting hyperglycemia. The resulting new (hIAPPxGKKO) line of mice had higher basal plasma glucose concentrations than the hIAPP transgenic mice at 3, 6, and 12 months of age (P < 0.05), as did GKKO mice compared with hIAPP transgenic mice at 6 and 12 months of age (P < 0.05). Basal plasma immunoreactive insulin (IRI) levels were lower in hIAPP x GKKO mice than in hIAPP transgenic mice at 6 months of age (P < 0.05). The area under the glucose curve in response to an intraperitoneal glucose challenge (1 g/kg body weight) was larger in hIAPPxGKKO mice than in hIAPP transgenic mice at 3, 6, and 12 months of age (P < 0.005) and in GKKO mice compared with hIAPP transgenic mice at 6 and 12 months of age (P < 0.005). The area under the IRI curve was lower in hIAPPxGKKO mice at 6 and 12 months of age (P < 0.05) than in hIAPP transgenic mice and in GKKO mice compared with hIAPP transgenic mice at 12 months of age (P < 0.05). Despite the presence of hyperglycemia, hIAPPxGKKO mice had a lower incidence (4 of 17 vs. 12 of 19, P < 0.05) and amount (0.40 +/- 0.24 vs. 1.2 +/- 0.3 arbitrary units, P < 0.05) of islet amyloid than hIAPP transgenic mice had. As expected, no islet amyloid was observed in GKKO mice lacking the hIAPP transgene (0 of 13). There was no difference in pancreatic content of IRI and hIAPP among the three groups of mice. Thus, despite the presence of impaired islet function and hyperglycemia, hIAPPxGKKO mice had a decreased incidence and quantity of islet amyloid. Therefore, our data suggest that impaired beta-cell glucose metabolism or hyperglycemia are not likely to contribute to islet amyloid formation in diabetes. Furthermore, this finding may explain the lack of progression of glycemia in patients with maturity-onset diabetes of the young.

Aging↗
PubMed2000

The constitutive secretory pathway is a major route for islet amyloid polypeptide secretion in neonatal but not adult rat islet cells.

Islet amyloid polypeptide (IAPP or amylin) is a normal secretory product of the pancreatic beta-cell that is cosecreted with insulin and is the major constituent of islet amyloid deposits in individuals with type 2 diabetes or insulinomas. We have previously reported that glucose stimulates IAPP, but not insulin secretion, from neonatal rat beta-cells when regulated secretion is prevented by use of calcium-free media, suggesting that IAPP secretion occurs via a constitutive secretory pathway. To directly test this hypothesis, we examined the effects of 2 substances-brefeldin A (BFA) and cycloheximide (CHX)-that are predicted to selectively block constitutive secretion on the release of IAPP-like immunoreactivity (IAPP-LI) and immunoreactive insulin (IRI) from neonatal rat islet cell monolayer cultures. When regulated release was prevented by use of calcium-free media, glucose-stimulated IAPP-LI release was nearly abolished by blocking constitutive release with 10 microg/ml BFA (mean +/- SD: 8.7 +/- 7.7 vs. 29.3 +/- 14.3 pmol/l; n = 5; P < 0.05), an inhibitor of constitutive vesicle formation. Similarly, calcium-independent, glucose-stimulated IAPP-LI secretion was markedly suppressed when new protein synthesis was blocked by administration of 20 microg/ml CHX (4.6 +/- 2.1 vs. 29.5 +/- 14.0 pmol/l; n = 5; P < 0.005). Secretion of IRI was low in the absence of calcium, and neither BFA nor CHX had any further effect. When calcium was added to the incubation media to allow regulated secretion of both IRI and IAPP-LI, both BFA (47.7 micro 8.7 vs. 80.7 micro 10.3 pmol/l; P < 0.001) and CHX (37.3 +/- 5.8 vs. 73.3 +/- 6.2 pmol/l; n = 5; P < 0.0001) inhibited glucose-stimulated IAPP-LI secretion by approximately 40%, but again had no inhibitory effect on IRI secretion. These data indicate that approximately 40% of glucose-stimulated IAPP-LI release occurs via a constitutive secretory pathway in neonatal rat islet cells. By contrast, in adult rat islets, glucose-stimulated IAPP-LI release was almost abolished in the absence of calcium (86 +/- 3% inhibition; P < 0.05) and unaffected by addition of BFA (275 +/- 28 vs. 205 +/- 89 pmol/l; NS) or CHX (160 +/- 20 vs. 205 +/- 89 pmol/l; NS), suggesting that constitutive secretion of IAPP does not occur in mature beta-cells. Collectively, these data suggest that a significant proportion of glucose-stimulated IAPP secretion from neonatal, but not adult, rat islet cells occurs via a constitutive secretory pathway.

Aging↗
PubMed2000

Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs.

Insulin transported from plasma into the central nervous system (CNS) is hypothesized to contribute to the negative feedback regulation of body adiposity. Because CNS insulin uptake is likely mediated by insulin receptors, physiological interventions that impair insulin action in the periphery might also reduce the efficiency of CNS insulin uptake and predispose to weight gain. We hypothesized that high-fat feeding, which both reduces insulin sensitivity in peripheral tissues and favors weight gain, reduces the efficiency of insulin uptake from plasma into the CNS. To test this hypothesis, we estimated parameters for cerebrospinal fluid (CSF) insulin uptake and clearance during an intravenous insulin infusion using compartmental modeling in 10 dogs before and after 7 weeks of high-fat feeding. These parameters, together with 24-h plasma insulin levels measured during ad libitum feeding, also permitted estimates of relative CNS insulin concentrations. The percent changes of adiposity, body weight, and food intake after high-fat feeding were each inversely associated with the percent changes of the parameter k1k2, which reflects the efficiency of CNS insulin uptake from plasma (r = -0.74, -0.69, -0.63; P = 0.015, 0.03, and 0.05, respectively). These findings were supported by a non-model-based calculation of CNS insulin uptake: the CSF-to-plasma insulin ratio during the insulin infusion. This ratio changed in association with changes of k1k2 (r = 0.84, P = 0.002), body weight (r = -0.66, P = 0.04), and relative adiposity (r = -0.72, P = 0.02). By comparison, changes in insulin sensitivity, according to minimal model analysis, were not associated with changes in k1k2, suggesting that these parameters are not regulated in parallel. During high-fat feeding, there was a 60% reduction of the estimated CNS insulin level (P = 0.04), and this estimate was inversely associated with percent changes in body weight (r = -0.71, P = 0.03). These results demonstrate that increased food intake and weight gain during high-fat feeding are associated with and may be causally related to reduced insulin delivery into the CNS.

Adipose Tissue↗
PubMed2000

Reduced beta-cell compensation to the insulin resistance associated with obesity in members of caucasian familial type 2 diabetic kindreds.

OBJECTIVE: Both obesity and a family history of diabetes reduce insulin sensitivity, but the impact of obesity on insulin secretion among individuals predisposed to diabetes is uncertain. We used a pedigree-based approach to test the hypothesis that beta-cell compensation to the insulin resistance associated with obesity is defective among individuals predisposed to diabetes by virtue of a strong family history of type 2 diabetes before the development of diabetes or glucose intolerance. RESEARCH DESIGN AND METHODS: A total of 126 members of 26 families ascertained for at least a sib pair with type 2 diabetes with onset before age 65 years underwent a tolbutamide-modified frequently sampled intravenous glucose tolerance test (FSIGT). Family members included 26 individuals with impaired glucose tolerance and 100 individuals with normal glucose tolerance (NGT). The acute insulin response to glucose (AIRglucose) was determined and insulin sensitivity (S(I)) estimated by minimal model analysis of FSIGT data. The beta-cell compensation for insulin sensitivity was estimated from the disposition index (DI), calculated as the product of S(I) and AIRglucose. Obesity was measured by BMI. RESULTS: Among all individuals, BMI was a significant predictor of both S(I) and AIRglucose, as expected. However, BMI also significantly predicted DI (P = 0.002) after correcting for age, sex, family membership, and glucose tolerance status. The relationship of BMI and DI was confirmed in 85 individuals with NGT who were aged <45 (P = 0.002) but not in 91 unrelated control individuals without a family history of diabetes. When normoglycemic individuals aged <45 were separated into three classes by BMI (< or =27, 27-30, >30), S(I) decreased progressively and significantly with obesity whereas AIRglucose rose significantly from lean to most obese classes. In contrast to the expectation of complete beta-cell compensation with obesity D1 fell significantly (P = 0.004) among obese family members. This relationship was not observed in control subjects. CONCLUSIONS: Individuals with a genetic predisposition to diabetes show a reduced beta-cell compensatory response to the reduced insulin sensitivity associated with obesity. We propose that this impaired compensation may be one manifestation of the underlying genetic defect in susceptible individuals. This finding helps explain the multiplicative effects of family history and obesity on risk of type 2 diabetes.

Aged↗
PubMed1999

Reduced beta-cell function contributes to impaired glucose tolerance in dogs made obese by high-fat feeding.

The ability to increase beta-cell function in the face of reduced insulin sensitivity is essential for normal glucose tolerance. Because high-fat feeding reduces both insulin sensitivity and glucose tolerance, we hypothesized that it also reduces beta-cell compensation. To test this hypothesis, we used intravenous glucose tolerance testing with minimal model analysis to measure glucose tolerance (K(g)), insulin sensitivity (S(I)), and the acute insulin response to glucose (AIR(g)) in nine dogs fed a chow diet and again after 7 wk of high-fat feeding. Additionally, we measured the effect of consuming each diet on 24-h profiles of insulin and glucose. After high-fat feeding, S(I) decreased by 57% (P = 0.003) but AIR(g) was unchanged. This absence of beta-cell compensation to insulin resistance contributed to a 41% reduction of K(g) (P = 0.003) and abolished the normal hyperbolic relationship between AIR(g) and S(I) observed at baseline. High-fat feeding also elicited a 44% lower 24-h insulin level (P = 0.004) in association with an 8% reduction of glucose (P = 0.0003). We conclude that high-fat feeding causes insulin resistance that is not compensated for by increased insulin secretion and that this contributes to the development of glucose intolerance. These effects of high-fat feeding may be especially deleterious to individuals predisposed to type 2 diabetes mellitus.

Animals↗