Y.-D. I. Chen

Insulin resistance and cigarette smoking.

Cigarette smoking is associated with increases in plasma triglycerides and decreases in plasma high density-lipoprotein-cholesterol concentration. These changes not only increase risk of coronary heart disease but also are secondary to resistance to insulin-stimulated glucose uptake or hyperinsulinaemia. To see whether there is a relation between cigarette smoking and insulin-mediated glucose uptake we measured plasma lipid and lipoprotein concentrations, plasma glucose and insulin response to an oral glucose challenge, and insulin-mediated glucose uptake in 40 matched healthy volunteers (20 non-smokers, 20 smokers). Smokers had significantly higher mean (SEM) very-low-density-lipoprotein triglycerides (0.66 [0.10] vs 0.39 [0.03] mmol/l, p less than 0.02) and cholesterol (0.45 [0.06] vs 0.23 [0.04] mmol/l, p less than 0.005) concentrations and lower high-density-lipoprotein cholesterol concentrations (1.16 [0.05] vs 1.51 [0.08] mmol/l, p less than 0.001). Although plasma glucose concentrations in response to the oral glucose load were similar in the two groups, plasma insulin response of the smokers was significantly higher (p less than 0.001). Finally, smokers had higher steady-state plasma glucose concentrations in response to a continuous infusion of glucose, insulin, and somatostatin (8.4 [0.2] vs 5.0 [0.3] mmol/l, p less than 0.001), despite similar steady-state plasma insulin concentrations. The findings show that chronic cigarette smokers are insulin resistant, hyperinsulinaemic, and dyslipidaemic compared with a matched group of non-smokers, and may help to explain why smoking increases risk of coronary heart disease.

A Comparison Between the Minimal Model and the Glucose Clamp in the Assessment of Insulin Sensitivity Across the Spectrum of Glucose Tolerance

An insulin-modified frequently sampled intravenous glucose tolerance test (FSIGTT) with minimal model analysis was compared with the glucose clamp in 11 subjects with normal glucose tolerance (NGT), 20 with impaired glucose tolerance (IGT), and 24 with non-insulin-dependent diabetes mellitus (NIDDM). The insulin sensitivity index (SI) was calculated from FSIGTT using 22- and 12-sample protocols (SI(22) and SI(12), respectively). Insulin sensitivity from the clamp was expressed as SI(clamp) and SIP(clamp). Minimal model parameters were similar when calculated with SI(22) and SI(12). SI could not be distinguished from 0 in ∼ 50% of diabetic patients with either protocol. SI(22) correlated significantly with SI(clamp) in the whole group (r = 0.62), and in the NGT (r = 0.53), IGT (r = 0.48), and NIDDM (r = 0.41) groups (P < 0.05 for each). SI(12) correlated significantly with SI(clamp) in the whole group (r = 0.55, P < 0.001) and in the NGT (r = 0.53, P = 0.046) and IGT (r = 0.58, P = 0.008) but not NIDDM (r = 0.30, P = 0.085) groups. When SI(22), SI(clamp), and SIP(clamp) were expressed in the same units, SI(22) was 66 ± 5% (mean ± SE) and 50 ± 8% lower than SI(clamp) and SIP(clamp), respectively. Thus, minimal model analysis of the insulin-modified FSIGTT provides estimates of insulin sensitivity that correlate significantly with those from the glucose clamp. The correlation was weaker, however, in NIDDM. The insulin-modified FSIGTT can be used as a simple test for assessment of insulin sensitivity in population studies involving nondiabetic subjects. Additional studies are needed before using this test routinely in patients with NIDDM.

Light-to-Moderate Alcohol Intake Is Associated With Enhanced Insulin Sensitivity

OBJECTIVE To test the hypothesis that insulin-mediated glucose uptake is enhanced in light-to-moderate alcohol consumption. RESEARCH DESIGN AND METHODS This is a case-control study of healthy volunteers, divided into nondrinkers and light-to-moderate drinkers based on their history of alcohol consumption. The study was performed at the General Clinical Research Center at Stanford University Medical Center and involved 40 volunteers, 20 men and 20 women. Measurements were made of the plasma glucose and insulin responses to an oral glucose challenge, fasting plasma lipid and lipoprotein concentrations, and steady-state plasma insulin (SSPI) and steady-state plasma glucose (SSPG) concentrations in response to a continuous infusion of somatostatin, insulin, and glucose. RESULTS Light-to-moderate drinkers (10-30 g/day) had lower integrated plasma glucose (17.8 ± 0.8 vs. 19.8 ± 0.9 mM/h, P < 0.02) and insulin (600 ± 65 vs. 1,075 ± 160 pM/h, P < 0.01) responses to the glucose challenge and higher fasting plasma high-density lipoprotein (HDL) cholesterol concentrations (1.46 ± 0.08 vs. 1.25 ± 0.08, P ± 0.02). Despite similar SSPI concentrations of ∼300 pM, SSPG concentrations were lower (P ± 0.01) in light-to-moderate drinkers (6.7 ± 0.8 vs. 10.7 ± 1.2 mM). Results were independent of age, body mass index, ratio of waist-to-hip girth, and estimates of level of habitual physical activity. CONCLUSIONS Light-to-moderate alcohol consumption in healthy men and women is associated with enhanced insulin-mediated glucose uptake, lower plasma glucose and insulin concentrations in response to oral glucose, and a higher HDLcholesterol concentration. The changes in glucose and insulin metabolism may contribute to the lower risk of coronary heart disease described in light-to-moderate drinkers.

Evaluation of octreotide to assess insulin-mediated glucose disposal by the insulin suppression test.

Dear Sir, Insulin resistance is commonly seen in patients with impaired glucose tolerance or non-insulin-dependent diabetes mellitus NIDDM, normoglycaemic first-degree relatives of patients with NIDDM, patients with high blood pressure and their normotensive first-degree relatives, dyslipidaemic individuals with high plasma triglyeeride and low HDL cholesterol concentrations, and both microvascular angina and conventional coronary heart disease [1-8]. Given these observations, it is not surprising that this phenomenon has received, and continues to receive considerable attention. In this context, plasma insulin concentration is often used as a surrogate marker for insulin-mediated glucose uptake. Although the relationship between plasma insulin concentration and insulin resistance is statistically significant in non-diabetic subjects [9], measurement of the plasma insulin level is not identical to the direct determination of insulin resistance, either quantitatively or conceptually. For approximately 20 years we have used a simple infusion procedure (insulin suppression test) to directly measure insulinmediated glucose uptake based upon the suppression of endogenous insulin secretion and the constant infusion of glucose and exogenous insulin [1-8]. Under these conditions, similar steady-state plasma insulin (SSPI) concentrations are reached in all individuals, and the steady-state plasma glucose (SSPG) concentration provides a direct estimate of insulin-mediated glucose uptake. More recently we have used somatostatin to suppress endogenous insulin secretion as initially suggested by Harano et al. [10]. Although this approach is satisfactory, it suffers from some practical drawbacks. For example, in the United States the use of somatostatin requires tiling for an investigative new drug number at the Food and Drug Administration. A specific grade of good manufacturing practice of this material must be purchased in bulk and prepared in aliquots for intravenous infusion. Furthermore, it is necessary to prove lack of pyrogenicity for these preparations. The present study was initiated in an effort to overcome these practical hurdles, and to simplify the use of the insulin suppression test to directly assess insulin resistance. Specifically, we compared the results of measuring insulin resistance with the commercially available somatostatin analogue, octreotide, and somatostatin. The study population consisted of 29 normal volunteers, 13 males and 16 females in good general health, taking no medication known to influence carbohydrate or lipid metabolism. They had a mean age of 46years (range 22-69) and a mean body mass index of 26.1 kg/mZ(range 18.6-35.4). Criteria for inclusion into the study included a normal medical history, physical examination, haemogram, and chemical screening battery. In addition, all subjects had a normal oral glucose tolerance test. This study was approved by the Stanford Human Subjects Committee, and each subject gave written informed consent. The insulin suppression test (IST) was performed in each volunteer on two occasions, between 2 days and 2 months apart. Volunteers were instructed not to change their usual diet or level of physical activity during the interval between the two tests, and there was no significant difference in their weight on the two oc-

Relationship between glucose tolerance, insulin secretion, and insulin action in non-obese individuals with varying degrees of glucose tolerance

SummaryPlasma glucose and insulin concentration following a 75 g oral glucose challenge and glucose uptake during a hyperinsulinaemic glucose clamp study were determined in 50 non-obese individuals. The study population was divided into five groups on the basis of their glucose tolerance: normal, impaired glucose tolerance, Type 2 (non-insulin-dependent) diabetes mellitus with fasting plasma glucose of less than 8 mmol/l, between 8–15 mmol/l, and more than 15 mmol/l. The plasma insulin response was significantly greater (p<0.001) than normal in those with either impaired glucose tolerance or Type 2 diabetes and a fasting plasma glucose concentration less than 8 mmol/l. In contrast, the plasma insulin response was similar to normal in the other two groups of patients with Type 2 diabetes, i.e. fasting plasma glucose concentration 8–15 mmol/l or greater than 15 mmol/l. Glucose uptake rates were significantly lower (p<0.001) than normal in subjects with impaired glucose tolerance and all three groups of patients with Type 2 diabetes. Although glucose uptake rates during the glucose clamp studies were relatively similar in all four groups of glucose intolerant subjects, the values were significantly lower in those patients with Type 2 diabetes who had a fasting plasma glucose concentration greater than 8 mmol/l (p<0.01), These data indicate that a significant degree of insulin resistance exists in patients with impaired glucose tolerance or Type 2 diabetes, relatively independent of fasting plasma glucose concentration. Indeed, glucose uptake during glucose clamp studies fell 8-fold over a range in fasting plasma glucose concentration of from 4.5 to 6.5 mmol/l. In contrast, the plasma insulin response increased over the same range of fasting plasma glucose concentrations. The fact that this defect in insulin action can be seen in patients who are hyperinsulinaemic, not hypoinsulinaemic, and only modestly hyperglycaemic, is consistent with the hypothesis that resistance to insulin-stimulate glucose uptake is a basic characteristic of patients with impaired glucose tolerance or Type 2 diabetes.

Relationship Between the Plasma Insulin Response to Oral Glucose and Insulin-stimulated Glucose Utilization in Normal Subjects

The relationship between in vivo insulin-stimulated glucose utilization (euglycemic clamp technique) and various estimates of the plasma insulin response to oral glucose was defined in 62 subjects with normal glucose tolerance. Both the incremental insulin increase above fasting (r = 0.61) and the total integrated insulin response (r = 0.65) were highly correlated (P < 0.001) with in vivo insulin action, and the relationship between total insulin response and insulin action remained significant (r = 0.61, P < 0.001) when corrected for variations in total glucose response, age, and obesity. In a subset of these subjects (N = 27) we were also able to assess state of habitual physical activity by estimating maximal oxygen consumption during bicycle ergometry. A significant correlation also existed between insulin action and response in these subjects (r = 0.67, P < 0.001), which remained significant (r = 0.65) when differences in total glucose response, obesity, age, and maximal oxygen consumption were taken into account. These data demonstrate that there is a significant correlation between insulin response and insulin action in normal individuals that can account for approximately one-third of the total variance in insulin action seen in subjects with normal glucose tolerance. Thus, determination of plasma insulin levels after an oral glucose challenge can only provide a qualitative estimate of insulin-stimulated glucose Utilization.

Relationships between plasma-free fatty acid concentration, endogenous glucose production, and fasting hyperglycemia in normal and non-insulin-dependent diabetic individuals☆

Measurements of fasting and postprandial plasma glucose, insulin, and free fatty acid (FFA) concentrations were made in 32 individuals--16 with normal glucose tolerance and 16 with non-insulin dependent diabetes mellitus (NIDDM)--further subdivided into two equal groups on the basis of body weight. In addition, endogenous glucose production was estimated in 32 subjects. Both fasting plasma glucose (251 +/- 14 v 86 +/- 1 mg/dL) and FFA (672 +/- 35 v 434 +/- 45 microEq/L) concentrations were significantly higher in patients with NIDDM (P less than .001), and the differences between normal and diabetic existed in both weight groups. Rates of endogenous glucose production were also significantly elevated (P less than .001) in diabetic (120 +/- 6 mg/m2 X min) as compared to normal subjects (73 +/- 6 mg/m2 X min), and these differences were also independent of degree of obesity. However, there were no significant differences between normal subjects and patients with NIDDM in either fasting or postprandial insulin concentrations. The similarity in insulin values for normal and diabetic subjects was true of both obesity groups, although insulin concentrations were somewhat higher in normal obese individuals as compared to their normal nonobese counterparts. Significant relationships were seen between values for fasting plasma glucose and endogenous glucose production (r = .89), fasting plasma glucose and fasting FFA (r = .64), and FFA levels and endogenous glucose production (r = .58) when all nonobese subjects were considered together. Essentially identical relationships, both qualitatively and quantitatively, were seen within the obese group.(ABSTRACT TRUNCATED AT 250 WORDS)

Deleterious metabolic effects of high-carbohydrate, sucrose-containing diets in patients with non-insulin-dependent diabetes mellitus

The effects of variations in dietary carbohydrate and fat intake on various aspects of carbohydrate and lipid metabolism were studied in patients with non-insulin-dependent diabetes mellitus (NIDDM). Two test diets were utilized, and they were consumed in random order over two 15-day periods. One diet was low in fat and high in carbohydrate, and corresponded closely to recent recommendations made by the American Diabetes Association (ADA), containing (as percent of total calories) 20 percent protein, 20 percent fat, and 60 percent carbohydrate, with 10 percent of total calories as sucrose. The other diet contained 20 percent protein, 40 percent fat, and 40 percent carbohydrate, with sucrose accounting for 3 percent of total calories. Although plasma fasting glucose and insulin concentrations were similar with both diets, incremental glucose and insulin responses from 8 a.m. to 4 p.m. were higher (p less than 0.01), and mean (+/- SEM) 24-hour urine glucose excretion was significantly greater (55 +/- 16 versus 26 +/- 4 g/24 hours p less than 0.02) in response to the low-fat, high-carbohydrate diet. In addition, fasting and postprandial triglyceride levels were increased (p less than 0.001 and p less than 0.05, respectively) and high-density lipoprotein (HDL) cholesterol concentrations were reduced (p less than 0.02) when patients with NIDDM ate the low-fat, high-carbohydrate diet. Finally, since low-density lipoprotein (LDL) concentrations did not change with diet, the HDL/LDL cholesterol ratio fell in response to the low-fat, high-carbohydrate diet. These results document that low-fat, high-carbohydrate diets, containing moderate amounts of sucrose, similar in composition to the recommendations of the ADA, have deleterious metabolic effects when consumed by patients with NIDDM for 15 days. Until it can be shown that these untoward effects are evanescent, and that long-term ingestion of similar diets will result in beneficial metabolic changes, it seems prudent to avoid the use of low-fat, high-carbohydrate diets containing moderate amounts of sucrose in patients with NIDDM.

Quantitative trait locus mapping of human blood pressure to a genetic region at or near the lipoprotein lipase gene locus on chromosome 8p22.

Resistance to insulin-mediated glucose disposal is a common finding in patients with non-insulin-dependent diabetes mellitus (NIDDM), as well as in nondiabetic individuals with hypertension. In an effort to identify the generic loci responsible for variations in blood pressure in individuals at increased risk of insulin resistance, we studied the distribution of blood pressure in 48 Taiwanese families with NIDDM and conducted quantitative sib-pair linkage analysis with candidate loci for insulin resistance, lipid metabolism, and blood pressure control. We found no evidence for linkage of the angiotensin converting enzyme locus on chromosome 17, nor the angiotensinogen and renin loci on chromosome 1, with either systolic or diastolic blood pressures. In contrast, we obtained significant evidence for linkage or systolic blood pressure, but not diastolic blood pressure, to a genetic region at or near the lipoprotein lipase (LPL) locus on the short arm of chromosome 8 (P = 0.002, n = 125 sib-pairs, for the haplotype generated from two simple sequence repeat markers within the LPL gene). Further strengthening this linkage observation, two flanking marker loci for LPL locus, D8S261 (9 cM telomeric to LPL locus) and D8S282 (3 cM centromeric to LPL locus), also showed evidence for linkage with systolic blood pressure (P = 0.02 and 0.0002 for D8S261 and D8S282, respectively). Two additional centromeric markers (D8S133, 5 cM from LPL locus, and NEFL, 11 cM from LPL locus) yielded significant P values of 0.01 and 0.001, respectively. Allelic variation around the LPL gene locus accounted for as much as 52-73% of the total interindividual variation in systolic blood pressure levels in this data set. Thus, we have identified a genetic locus at or near the LPL gene locus which contributes to the variation of systolic blood pressure levels in nondiabetic family members at high risk for insulin resistance and NIDDM.

Why Do Low-Fat High-Carbohydrate Diets Accentuate Postprandial Lipemia in Patients With NIDDM?

OBJECTIVE To understand why low-fat high-carbohydrate (CHO) diets lead to higher fasting and postprandial concentrations of triglyceride (TG)-rich lipoproteins in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS Patients with NIDDM were placed randomly on diets containing either 55% CHO, 30% fat, and 15% protein or 40% CHO, 45% fat, and 15% protein for 6 weeks, followed by crossover to the other diet. Test meals at the end of each diet period were consumed at 8:00 A.M. and 12:00 P.M. (noon) and contained 20 and 40% of daily calories, respectively. Vitamin A was also given at noon, and TG-rich lipoproteins of intestinal origin were identified by the presence of vitamin A esters. Frequent measurements were made throughout the 24-h study period of plasma glucose, insulin, and TG concentrations. Plasma samples obtained from 12:00 P.M. (noon) until 12 A.M. (midnight) were subjected to ultracentrifugation, and measurements were made of TG and vitamin A ester concentrations in plasma and in both the Svedberg flotation constant (Sf) >400 (chylomicron) and Sf 20-400 (chylomicron remnant) lipoprotein fractions. In addition, very-low-density lipoprotein (VLDL)-TG turnover rate was estimated by following the decay of [3H]VLDL-TG. Finally, postheparin lipoprotein lipase and hepatic lipase activities were measured at the end of each dietary period. RESULTS Mean ± SE hourly concentrations of glucose (8.0 ± 0.8 vs. 7.5 ± 0.7 mmol/1), insulin (184 ± 26 vs. 158 ± 19 pmol/1), and TG (2.8 ± 0.2 vs. 2.1 ± 0.2 mmol/1) were higher (P < 0.05-0.001) after the 55% CHO diet. The 55% CHO diet also led to an increase (P < 0.05-0.01) in the mean ± SE hourly concentrations of vitamin A esters in plasma (2.3 ± 0.3 vs. 1.6 ±0.1 μmol/l) and in both the chylomicron (2.0 ± 0.3 vs. 1.4 ±0.1 μmol/l) and chylomicron remnant fractions (0.36 ± 0.04 vs. 0.14 ± 0.03 μmol;/l). In addition, the VLDL-TG production rate was higher (17.2 ± 1.4 vs. 12.8 ± 1.0 mg · kg−1 · h−1, P < 0.003) and the VLDL-TG fractional catabolic rate lower (0.22 ± 0.02 to 0.28 ± 0.02 l/h, P < 0.005) after the 55% CHO diet. Finally, there was an increase in lipoprotein lipase activity (7.0 ± 0.8 to 8.1 ± 0.7 μmol free fatty acids released · ml−1 · h−1, P < 0.02) in response to the CHO-enriched diet. CONCLUSIONS A low-fat high-CHO diet in patients with NIDDM led to 1) higher day-long plasma glucose, insulin, and TG concentrations; 2) postprandial accumulation of TG-rich lipoproteins of intestinal origin; 3) increased production of VLDL-TG; and 4) increased postheparin lipoprotein lipase activity. These data provide a mechanism for the hypertriglycer-idemic effect of CHO-enriched diets in patients with NIDDM and demonstrate that multiple risk factors for coronary heart disease are accentuated when these individuals consume diets recommended to reduce this risk.