Bile acid changes after metabolic surgery are linked to improvement in insulin sensitivity.

BACKGROUND: Metabolic surgery is associated with a prompt improvement in insulin resistance, although the mechanism of action remains unknown. The literature on bile acid changes after metabolic surgery is conflicting, and insulin sensitivity is generally assessed by indirect methods. The aim of this study was to investigate the relationship between improvement in insulin sensitivity and concentration of circulating bile acids after biliopancreatic diversion (BPD) and Roux-en-Y gastric bypass (RYGB). METHODS: This was a prospective observational study of nine patients who underwent BPD and six who had RYGB. Inclusion criteria for participation were a BMI in excess of 40 kg/m2 , no previous diagnosis of type 2 diabetes and willingness to participate. Exclusion criteria were major endocrine diseases, malignancies and liver cirrhosis. Follow-up visits were carried out after a mean(s.d.) of 185·3(72·9) days. Fasting plasma bile acids were assessed by ultra-high-performance liquid chromatography coupled with a triple quadrupole mass spectrometer, and insulin sensitivity was measured by means of a hyperinsulinaemic-euglycaemic clamp. RESULTS: A significant increase in all bile acids, as well as an amelioration of insulin sensitivity, was observed after metabolic surgery. An increase in conjugated secondary bile acids was significantly associated with an increase in insulin sensitivity. Only the increase in glycodeoxycholic acid was significantly associated with an increase in insulin sensitivity in analysis of individual conjugated secondary bile acids. CONCLUSION: Glycodeoxycholic acid might drive the improved insulin sensitivity after metabolic surgery.

Gender-specific differences in carotid intima-media thickness and its progression over three years: a multicenter European study.

BACKGROUND AND AIMS: This multicentre European study evaluated, in a young-to-middle-aged healthy population without carotid atherosclerosis, the gender-related differences in carotid intima-media thickness (IMT) and its short-term (3-year) progression, and whether these differences are related to different vascular ageing rate, cardiovascular risk profile or different susceptibility to family predisposition to cardiovascular diseases (CVD). METHODS AND RESULTS: 366 men and 422 women (age between 30 and 60 years) underwent B-mode carotid ultrasound at baseline and after 3-year follow-up period. IMT in 3 carotid segments was higher in men than in women (p < 0.0001 for all segments). When evaluated according to age decade, differences between men and women disappeared in the 6th decade, as in this decade a 3-year IMT progression rate accelerated in women (p < 0.05 as compared to the 4th and 5th age decade). Age was a major determinant of baseline all-segment IMT in women; in men all-segment IMT was influenced by age and LDL-cholesterol. IMT progression did not correlate with established cardiovascular risk factors, their short-term changes or family predisposition to CVD. Yet, a 3-year IMT progression in common carotid artery (CCA) was higher in men (p = 0.01) and women (p < 0.01) in whom relative Framingham risk increased during the corresponding period. CONCLUSION: This study provides reference values on IMT and its short-term progression in healthy young-to-middle-aged population, and demonstrates gender-related differences in the susceptibility of carotid wall to ageing and LDL-cholesterol. Increase in Framingham risk accelerated a short-term CCA IMT progression rate in both genders, whereas family predisposition to CVD did not influence carotid IMT.

Estimating insulin sensitivity and beta cell function: perspectives from the modern pandemics of obesity and type 2 diabetes.

The 1985 manuscript describing the HOMA model, by Matthews and colleagues, is the most cited paper in the history of Diabetologia. In this edition of 'Then and now' we assess the impact of this seminal paper by considering the contribution of this elegant work in the context of the most rapidly changing period in the history of diabetes. HOMA was born in the middle of an 'era' of insulin resistance, and was subsequently nurtured and grew during the 'eras' of insulin sensitisers and diabetes prevention. From the modern era of insulin resistance onward, researchers have sought a convenient method for measuring insulin sensitivity and secretion, and found this in HOMA. However, the explosion in the prevalence of diabetes clearly underlines that an understanding of insulin resistance and how it can be measured has been insufficient to make any impact on the growing pandemic of diabetes. Knowledge of individual physiology is important, but the dramatic impact of the modern environment may be the factor that has escaped attention until very recently. An optimist can only state that the coming 'era' in diabetes research will be a period of true translation of scientific insight and implementation of effective disease prevention.

Correlation of the leptin:adiponectin ratio with measures of insulin resistance in non-diabetic individuals.

AIMS/HYPOTHESIS: Obesity is the dominant cause of insulin resistance. In adult humans it is characterised by a combination of adipocyte hypertrophy and, to a lesser extent, adipocyte hyperplasia. As hypertrophic adipocytes secrete more leptin and less adiponectin, the plasma leptin:adiponectin ratio (LAR) has been proposed as a potentially useful measure of insulin resistance and vascular risk. We sought to assess the usefulness of the LAR as a measure of insulin resistance in non-diabetic white adults. METHODS: Leptin and adiponectin levels were measured in 2,097 non-diabetic individuals from the Ely and European Group for the Study of Insulin Resistance (EGIR) Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study cohorts. LAR was compared with fasting insulin and HOMA-derived insulin sensitivity (HOMA-S) in all individuals and with the insulin sensitivity index (M/I) from hyperinsulinaemic-euglycaemic clamp studies in 1,226 EGIR RISC participants. RESULTS: The LAR was highly correlated with HOMA-S in men (r = -0.58, p = 4.5 x 10(-33) and r = -0.65, p = 1.1 x 10(-66) within the Ely and EGIR RISC study cohorts, respectively) and in women (r = -0.51, p = 2.8 x 10(-36) and r = -0.61, p = 2.5 x 10(-73)). The LAR was also strongly correlated with the clamp M/I value (r = -0.52, p = 4.5 x 10(-38) and r = -0.47, p = 6.6 x 10(-40) in men and women, respectively), similar to correlations between HOMA-S and the M/I value. CONCLUSIONS/INTERPRETATION: The leptin:adiponectin ratio is a useful measure of insulin resistance in non-diabetic white adults. These data highlight the central role of adipocyte dysfunction in the pathogenesis of insulin resistance. Given that variations between fasting and postprandial leptin and adiponectin levels tend to be small, the leptin to adiponectin ratio might also have potential value in assessing insulin sensitivity in the non-fasted state.

Adverse metabolic profiles in a cohort of obese Irish children.

BACKGROUND: The metabolic characteristics of obese Irish children are not well defined. We prospectively examined the relationship between the degree of obesity and glucose metabolism, insulin sensitivity and suspected non-alcoholic steatohepatosis (NASH) in a pilot study of obese Irish children. METHODS: We measured height, weight, body mass index (BMI), blood pressure, waist and hip circumference in 18 participants (mean age 15.5 years). Fasting blood glucose, insulin, lipid profile and alanine aminotransferase (ALT) concentrations were also measured. A standard 75 g oral glucose tolerance test was performed and insulin sensitivity was derived from this using a mathematical model--oral glucose insulin sensitivity. RESULTS: There were significant associations between the degree of obesity, insulin sensitivity and markers of liver steatosis. For example, when adjusted for pubertal status, there were significant associations between standardized BMI and insulin sensitivity (regression coefficient, beta = -70.1, P = 0.018) and ALT (beta = 20.7, P = 0.007). CONCLUSION: This study suggests that the degree of obesity is associated with lower insulin sensitivity and possible NASH in obese Irish children.

Immigrant patients with type 2 diabetes mellitus have poorer initial and on-going glycemic control than a matched population of Irish patients.

We compared the glycemic and cardiovascular risk status of non-Caucasian patients with type 2 diabetes mellitus (T2DM) who recently emigrated to Ireland with a matched population of Irish patients. We identified 105 non-Caucasian patients with T2DM who recently emigrated to Ireland and compared them with 105 Irish patients with T2DM, who were matched for age, sex and duration of diabetes. Immigrants with T2DM had significantly worse initial (9.8% vs 9.1%, p<0.05) and on-going (8.3% vs 7.1, p<0.05) glycemic control and higher microalbumin to creatinine ratio compared to the Irish patients. A greater proportion of immigrants with T2DM were on insulin therapy for their diabetes. Irish patients had significantly higher fasting triglyceride concentrations compared to the immigrants (1.9+/-0.1 mmol/l vs 1.6+/-0.1 mmol/l, p<0.05). This vulnerable population of immigrants with T2DM is currently at higher risk of complications of diabetes and warrants greater attention to glycemic control and control of other risk factors.

A noninvasive method to measure splanchnic glucose uptake after oral glucose administration.

We have developed a noninvasive method to estimate splanchnic glucose uptake (SGU) in humans (oral glucose clamp technique [OG-CLAMP]), which combines a hyperinsulinemic clamp with an oral glucose load (oral glucose tolerance test). We validated this method in 12 nondiabetic subjects using hepatic vein catheterization (HVC) during an oral glucose tolerance test. During HVC, splanchnic blood flow increased from 1,395 +/- 64 to 1,935 +/- 109 ml/min, returning to basal after 180 min and accounted for 45 +/- 7% of SGU in lean and 19 +/- 5% in obese subjects (P < 0.05). SGU estimated during the OG-CLAMP was 22 +/- 2% of the glucose load, and this was significantly correlated (r = 0.90, P < 0.0001) with SGU (35 +/- 4%) and with first pass SGU (24 +/- 3%; r = 0.83, P < 0.001) measured during HVC. SGU was higher in obese than in lean subjects during OG-CLAMP (27 +/- 1% vs 18 +/- 3%, P < 0.01) and HVC (44 +/- 4% vs 26 +/- 5%, P < 0.05). In conclusion, SGU during the OG-CLAMP is well correlated to SGU measured during HVC. An increase in splanchnic blood flow is a major contributor to SGU in lean subjects. SGU is increased in obese subjects as measured by both methods.

Evidence for decreased splanchnic glucose uptake after oral glucose administration in non-insulin-dependent diabetes mellitus.

The role of splanchnic glucose uptake (SGU) after oral glucose administration as a potential factor contributing to postprandial hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) has not been established conclusively. Therefore, we investigated SGU in six patients with NIDDM and six weight-matched control subjects by means of the hepatic vein catheterization (HVC) technique. In a second part, we examined the applicability of the recently developed OG-CLAMP technique in NIDDM by comparing SGU and first-pass SGU during HVC with SGU during the OG-CLAMP experiment. The OG-CLAMP method combines a euglycemic, hyperinsulinemic clamp and an oral glucose tolerance test (75 g) during steady state glucose infusion (GINF). During HVC, SGU equals the splanchnic fractional extraction times the total (oral and arterial) glucose load presented to the liver. For OG-CLAMP, SGU was calculated as first-pass SGU by subtracting the integrated decrease in GINF over 180 min from 75 g. Cumulative splanchnic glucose output after oral glucose correlated significantly between both methods and was increased significantly in NIDDM patients (73.1+/-5.1 g for HVC, 76.5+/-5.5 for OG-CLAMP) compared with nondiabetic patients (46.7+/-4.4 g for HVC, 57.5+/-1.9 for OG-CLAMP). Thus, in NIDDM patients, SGU (7.4+/-2.1 vs. 37.8+/-5.9% in nondiabetic patients, P < 0.001) and first-pass SGU (4.7+/-1.7 vs. 26.5+/-5.1% in nondiabetic patients, P < 0.01) were decreased significantly during HVC, as was SGU during OG-CLAMP (3.9+/-1.7 vs. 23.4+/-2.5% in nondiabetic patients, P < 0.0001). SGU measured during OG-CLAMP correlated significantly with SGU (r = 0.87, P < 0.05 for NIDDM patients; r = 0.94, P < 0.01 for nondiabetic patients) and first-pass SGU (r = 0.87, P < 0.05 for NIDDM patients; r = 0.84, P < 0.05 for nondiabetic patients) during HVC. In conclusion, (a) SGU after oral glucose administration is decreased in NIDDM as measured by both methods, and (b) SGU during the OG-CLAMP is well-correlated to SGU and first-pass SGU during HVC in NIDDM. The decrease in SGU in NIDDM might contribute to postprandial hyperglycemia in diabetic subjects.

The cost of treating type 2 diabetes (CODEIRE).

Diabetes mellitus is the most common chronic metabolic disease and a major source of morbidity and mortality. Type 2 diabetes (T2D) is by far the most prevalent form of diabetes accounting for around 90% of cases worldwide. In recent years it has become apparent that a diabetes epidemic is unfolding as a result of increasing obesity, sedentary lifestyles and an ageing population. The enormity of the diabetes epidemic raises concern about the total cost to healthcare systems. This study was undertaken to investigate the direct healthcare costs of managing T2D in Ireland. Data was captured on 701 diabetes patients attending four diabetes centres. A bottom-up, prevalence-based design was used, which collected data on hospital resource use and clinical outcome measures over a 12-month period (1999/2000). The study was observational in nature, focusing on usual care of patients with T2D. Although the true prevalence of T2D in Ireland is unknown, conservative estimates are 3.9% for diagnosed diabetes and 6% for both diagnosed and undiagnosed diabetes. Using these figures the annual total direct cost was estimated at 377.2 million euro for diagnosed diabetes and 580.2 million euro for both diagnosed and undiagnosed diabetes. This corresponds to 4.1% and 6.4% of total healthcare expenditure respectively. Hospitalisations were the main driver of costs, accounting for almost half of overall costs, while ambulatory and drug costs accounted for 27% and 25% respectively. Hospitalisation costs were high because 60% of patients had developed complications. The most common microvascular and macrovascular complications were neuropathy and angina respectively. The annual cost of care for patients with microvascular and macrovascular complications were 1.8 and 2.9 times the cost of treating those without clinical evidence of complications respectively. The figure for patients with both types of complications was 3.8. This study shows that T2D is a very costly disease, largely due to the cost of and the management of complications. Many diabetes related complications are preventable, therefore it would appear a cost-effective approach for government to invest in the prevention of T2D and diabetes related complications.

Mechanisms of the kinetic defect in insulin action in obesity and NIDDM.

To evaluate kinetic defects in insulin action, we performed time-course studies during hyperinsulinemic (120 mU x m(-2) x min(-1)) isoglycemic clamps in seven subjects with NIDDM (194 +/- 29 mg/dl) and in seven lean and seven obese nondiabetic subjects. The time course of whole-body glucose disposal rate (GDR), leg glucose uptake (LGU), hepatic glucose output (HGO), and muscle insulin receptor tyrosine kinase (IRTK) activation were measured. The obese and NIDDM subjects had marked delays in activation of GDR (T50 74 +/- 14 and 95 +/- 15 min, respectively, compared with 33 +/- 2 min in lean control subjects), arteriovenous glucose difference (T50 80 +/- 12 and 109 +/- 31 min compared with 30 +/- 3 min) and LGU (T50 89 +/- 25 and 98 +/- 27 min compared with 29 +/- 4 min). All three measurements reached normal levels in the NIDDM group after 4-5 h of insulin infusion. Although only a limited number of data points could be obtained from serial muscle biopsies, no delay in the rate of activation of IRTK was apparent in the obese and NIDDM groups. In conclusion, 1) in obese and NIDDM subjects, insulin-mediated GDR and LGU are delayed to a similar degree; 2) mass action normalizes GDR and LGU in NIDDM, but only after several hours of insulin infusion; and 3) The kinetic defect in NIDDM and obesity most likely involves intracellular loci distal to activation of the insulin receptor kinase.

Effect of obesity on insulin resistance in normal subjects and patients with NIDDM.

Insulin resistance (IR) is a characteristic feature of non-insulin-dependent diabetes mellitus (NIDDM) as well as obesity, and a majority of NIDDM patients are obese. To assess the effect of obesity independent of NIDDM on IR, we studied the relationship between IR and obesity in 65 normal and 58 NIDDM subjects; we used body mass index (BMI) as a measure of obesity and glucose infusion rate (GINF) during a euglycemic hyperinsulinemic (120 mU.m-2.min-1) glucose clamp as a measure of IR. In lean normal subjects, GINF was 57.7 +/- 2.2 mumol.kg-1.min-1 (10.4 +/- 0.4 mg.kg-1.min-1) and the lean NIDDM subjects were markedly insulin-resistant, with a GINF of 34.4 +/- 2.8 mumol.kg-1.min-1 (6.2 +/- 0.5 mg.kg-1.min-1). Obese normal subjects were also insulin-resistant compared with lean normal subjects, with a GINF of 36.1 +/- 2.2 mumol.kg-1.min-1 (6.5 +/- 0.4 mg.kg-1.min-1), and obesity caused an increase in IR in NIDDM, with a GINF of 21.1 +/- 1.4 mumol.kg-1.min-1 (3.8 +/- 0.25 mg.kg-1.min-1) in the obese NIDDM subjects. Therefore, approximately 61% of the IR in obese NIDDM subjects is due to NIDDM, with 39% due to obesity, demonstrating a greater impact of NIDDM than of obesity in causing IR. The correlation between GINF and BMI was much better in normal subjects (r = -0.75) than in NIDDM subjects (r = -0.50) as was the relationship between fasting insulin level and BMI (r = -0.59 in normal subjects, r = -0.48 in NIDDM subjects). As expected, the fasting insulin level was also strongly correlated to GINF in normal subjects (r = -0.61); however, this relationship was weaker in NIDDM subjects ( r = -0.46). In conclusion, 1) obesity has a major impact to cause insulin resistance in nondiabetic subjects, but the effect of obesity on IR in NIDDM is less; 2) NIDDM per se is the major contributor to IR in NIDDM; and 3) the fasting insulin level is a better surrogate marker of IR in nondiabetic subjects than in NIDDM patients.

Effect of troglitazone on leptin production. Studies in vitro and in human subjects.

Leptin, the product of the ob gene, is a hormone secreted by adipocytes. Animals with mutations in the ob gene are obese and lose weight when given leptin, but little is known about the physiological role of leptin in humans. Obese subjects have higher concentrations of leptin than lean subjects, the strongest correlation being with percentage body fat. Thus, it appears that obese subjects are resistant to the effects of endogenously secreted leptin. We have also shown that insulin stimulates leptin production, chronically but not acutely, presumably through its trophic effect on adipocytes. Troglitazone is an insulin-sensitizing thiazolidinedione, which improves hepatic and skeletal muscle insulin resistance in NIDDM and obesity. This study was undertaken to investigate the effects of troglitazone on leptin production in vitro and in vivo. In the presence and absence of 100 nmol/l insulin and 10 umol/l troglitazone, 72-h primary cultures of isolated abdominal adipocytes were studied. Insulin led to an almost twofold increase in leptin in vitro, and this increase was completely abolished by coincubation with troglitazone. Incubation with troglitazone alone led to a 40% decrease in leptin production. In obese patients administered troglitazone 200 mg twice daily for 12 weeks, there was no significant change in fasting plasma leptin concentrations, despite a 40-50% reduction in fasting and postmeal plasma insulin concentrations. Troglitazone treatment led to a significant increase in insulin sensitivity, and there was a positive correlation between the change in insulin sensitivity and the change in plasma leptin concentration in these subjects. In conclusion, troglitazone treatment had no net effect on plasma leptin concentrations, possibly because of improvement in insulin sensitivity and reduction in plasma insulin concentrations.

Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro.

This study was undertaken to investigate the changes in obesity (OB) gene expression and production of leptin in response to insulin in vitro and in vivo under euglycemic and hyperglycemic conditions in humans. Three protocols were used: 1) euglycemic clamp with insulin infusion rates at 40, 120, 300, and 1,200 mU / m / min carried out for up to 5 h performed in 16 normal lean individuals, 30 obese individuals, and 31 patients with NIDDM; 2) 64-to 72-h hyperglycemic (glucose 12.6 mmol/l) clamp performed on 5 lean individuals; 3) long-term (96-h) primary culture of isolated abdominal adipocytes in the presence and absence of 100 nmol/l insulin. Short-term hyperinsulinemia in the range of 80 to > 10,000 microU/ml had no effect on circulating levels of leptin. During the prolonged hyperglycemic clamp, a rise in leptin was observed during the last 24 h of the study (P < 0.001). In the presence of insulin in vitro, OB gene expression increased at 72 h (P < 0.01), followed by an increase in leptin released to the medium (P < 0.001). In summary, insulin does not stimulate leptin production acutely; however, a long-term effect of insulin on leptin production could be demonstrated both in vivo and in vitro. These data suggest that insulin regulates OB gene expression and leptin production indirectly, probably through its trophic effect on adipocytes.

A model-based method for assessing insulin sensitivity from the oral glucose tolerance test.

OBJECTIVE: Available insulin sensitivity (IS) methods based on the oral glucose tolerance test (OGTT) are empirical. We used a glucose-insulin model to derive an OGTT-based IS (oral glucose insulin sensitivity [OGIS]) index, which predicts glucose clearance in a glucose clamp. We validated OGIS against clamp data. RESEARCH DESIGN AND METHODS: OGIS requires glucose and insulin concentrations from a 75-g OGTT at 0, 2, and 3 h (3-h OGTT) or at 0, 1.5, and 2 h (2-h OGTT). The formula includes six constants optimized to match the clamp results. For this purpose, 15 lean nondiabetic subjects (BMI < 25 kg/m2), 38 obese nondiabetic subjects (BMI > 25 kg/m2), and 38 subjects with type 2 diabetes randomly underwent an OGTT and a 120 mU x min(-1) x m(-2) insulin infusion euglycemic clamp. Glucose clearance (Cl CLAMP), calculated as the ratio of glucose infusion to concentration during the last hour of the clamp, was compared with OGIS. OGIS was also tested on an independent group of 13 subjects with impaired glucose tolerance (IGT). RESULTS: OGIS and Cl CLAMP were correlated in the whole group (R = 0.77, P < 0.0001), in the subgroups (lean: R = 0.59; obese: R = 0.73; type 2 diabetes: R = 0.49; P < 0.02), and in the independent IGT group (R = 0.65, P < 0.02). Reproducibility of OGIS and Cl CLAMP were similar (coefficients of variation: OGIS 7.1%, Cl CLAMP 6.4%). OGIS was as effective as Cl CLAMP in discriminating between groups (for OGIS, lean vs. obese: 440 +/- 16 vs. 362 +/- 11 ml x min(-1) x m(-2), p < 0.001; lean vs. type 2 diabetes: 440 +/- 16 vs. 239 +/- 7, P < 0.0001; obese vs. type 2 diabetes: 362 +/- 11 vs. 239 +/- 7, P < 0.0001; results were similar for Cl CLAMP). The relationships between IS and BMI, fasting plasma insulin, and insulin secretion (calculated from the OGTT insulin concentration) were examined. OGIS yielded results similar to Cl CLAMP and fully consistent with established physiological principles. The performance of the index for the 3-h and 2-h OGTT was similar. CONCLUSIONS: OGIS is an index of IS in good agreement with the clamp. Because of its simplicity (only three blood samples required), this method has potential use for clinical investigation including large-scale epidemiological studies.

Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects.

OBJECTIVE: To study the metabolic effects of a new oral antidiabetic agent, CS-045, in subjects with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Eleven NIDDM subjects (mean age 59 yr and body mass index 32.3) were treated with 400 mg/day CS-045 for 6-12 wk. Patients were hospitalized before and at the end of the drug-treatment period for metabolic studies, including oral glucose tolerance test (OGTT), meal tolerance test (MTT), euglycemic glucose-clamp studies, and lipid analyses. RESULTS: Eight subjects showed a marked clinical response to the drug, whereas 3 were nonresponders. The data were analyzed both for the total group and for the responders. Fasting plasma glucose (FPG) fell from 12.5 +/- 0.7 to 10.7 +/- 1.0 mM in the total group but fell more dramatically from 12.7 +/- 0.5 to 8.3 +/- 0.6 mM in the responder group. The area under the OGTT glucose curve improved by 17% in the total group and by 29% in the responders. The area under the MTT glucose curve improved by 38 and 52%, respectively. MTT levels of insulin, free fatty acids, and glucagon were significantly lower after treatment. Glucose disposal rates during glucose-clamp studies were increased in all subjects after CS-045 treatment. Mean increases were 63% at 120 mU.m-2.min-1 and 41% at 300 mU.m-2.min-1. Basal hepatic glucose production fell by 17% in the total group and by 28% in the responders. CONCLUSIONS: CS-045 improves insulin resistance, reduces insulinemia, lowers hepatic glucose production, and improves both fasting and postprandial glycemia in NIDDM subjects. CS-045 may represent a new therapeutic option for NIDDM.

Role of human skeletal muscle insulin receptor kinase in the in vivo insulin resistance of noninsulin-dependent diabetes mellitus and obesity.

To assess the role of insulin receptor (IR) tyrosine kinase in human insulin resistance, we examined the kinase activity of IR of skeletal muscle biopsies from eight lean and five obese nondiabetics and six obese subjects with noninsulin-dependent diabetes mellitus (NIDDM). Biopsies were taken during euglycemic clamps at insulin infusion rates of 0, 40, 120, and 1200 mU/m2.min. IRs were immobilized on insulin agarose beads, and autophosphorylation and histone 2B phosphorylation were measured. Phosphatase and protease inhibitors preserved the in vivo phosphorylation state of the IRs. Glucose disposal rates (GDR) were reduced according to insulin dose by 23-30% in the obese (P < 0.05) and 43-64% in the NIDDM subjects (P < 0.0005). IR autophosphorylation was increased up to 9-fold in controls and was reduced (P = 0.04) in NIDDM compared to obese subjects. Histone-2B kinase was increased up to 6-fold in controls and was reduced by 50% in NIDDM. Kinase values by both methods were similar in lean and obese controls. In vivo stimulation of kinase was well correlated to the increase in GDR, as was the decrement in kinase in NIDDM to the decrement in GDR. These results suggest that defects in muscle IR kinase are significant in the in vivo insulin resistance of NIDDM, but not that of obesity.

Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age.

Aging in humans is accompanied by a progressive decline in the secretion of the adrenal androgens dehydroepiandrosterone (DHEA) and DHEA sulfate (DS), paralleling that of the GH-insulin-like growth factor-I (GH-IGF-I) axis. Although the functional relationship of the decline of the GH-IGF-I system and catabolism is recognized, the biological role of DHEA in human aging remains undefined. To test the hypothesis that the decline in DHEA may contribute to the shift from anabolism to catabolism associated with aging, we studied the effect of a replacement dose of DHEA in 13 men and 17 women, 40-70 yr of age. A randomized placebo-controlled cross-over trial of nightly oral DHEA administration (50 mg) of 6-month duration was conducted. During each treatment period, concentrations of androgens, lipids, apolipoproteins, IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, insulin sensitivity, percent body fat, libido, and sense of well-being were measured. A subgroup of men (n = 8) and women (n = 5) underwent 24-h sampling at 20-min intervals for GH determinations. DHEA and DS serum levels were restored to those found in young adults within 2 weeks of DHEA replacement and were sustained throughout the 3 months of the study. A 2-fold increase in serum levels of androgens (androstenedione, testosterone, and dihydrotestosterone) was observed in women, with only a small rise in androstenedione in men. There was no change in circulating levels of sex hormone-binding globulin, estrone, or estradiol in either gender. High density lipoprotein levels declined slightly in women, with no other lipid changes noted for either gender. Insulin sensitivity and percent body fat were unaltered. Although mean 24-h GH and IGFBP-3 levels were unchanged, serum IGF-I levels increased significantly, and IGFBP-1 decreased significantly for both genders, suggesting an increased bioavailability of IGF-I to target tissues. This was associated with a remarkable increase in perceived physical and psychological well-being for both men (67%) and women (84%) and no change in libido. In conclusion, restoring DHEA and DS to young adult levels in men and women of advancing age induced an increase in the bioavailability of IGF-I, as reflected by an increase in IGF-I and a decrease in IGFBP-1 levels. These observations together with improvement of physical and psychological well-being in both genders and the absence of side-effects constitute the first demonstration of novel effects of DHEA replacement in age-advanced men and women.

Insulin resistance and non-insulin-dependent diabetes mellitus: cellular and molecular mechanisms.

Non-insulin-dependent diabetes mellitus is a complex metabolic disorder that involves numerous biochemical abnormalities, a heterogenous clinical picture, and a polygenic hereditary component. The pathophysiologic state involves increased basal hepatic glucose production, decreased insulin-mediated glucose utilization in target tissues, and altered pancreatic function with decreased beta cell function and enhanced glucagon secretion. Prospective studies indicate that insulin resistance and hyperinsulinemia exist in the prediabetic state at a time when glucose tolerance is normal. When hyperglycemia supervenes, both insulin secretion and insulin-mediated glucose utilization are further compromised, mediated in part by sustained hyperglycemia itself. Insulin resistance may occur at any level in the biologic action of insulin, from initial binding to cell surface receptors to the phosphorylation cascade that is initiated by autophosphorylation of the insulin receptor. Receptors isolated from patients with non-insulin-dependent diabetes mellitus have compromised autophosphorylation-kinase activity when isolated from adipocytes, liver, erythrocytes, and skeletal muscle. The magnitude of the decrease in insulin receptor kinase activity is correlated with the degree of fasting hyperglycemia. However, the defect in insulin receptor kinase activity is normalized after weight reduction or other measures that reduce hyperglycemia, indicating the secondary nature of the defect. Clarification of the mechanisms underlying insulin resistance in non-insulin-dependent diabetes mellitus will lead to new treatment modalities for this disease.