Martin M.T. Fuh

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.

Resistance to insulin-mediated glucose uptake and hyperinsulinemia in women who had preeclampsia during pregnancy

Plasma glucose and insulin responses to a 75-g oral glucose load, and the steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations after an infusion of somatostatin, insulin, and glucose, were determined 2 months after delivery in 26 women; 13 who had a normal pregnancy and 13 who developed preeclampsia. The plasma glucose response to oral glucose was not different in the two groups, but the plasma insulin response was significantly greater (P < .02) in those who had been preeclamptic. Although the mean (+/- SE) SSPI concentrations during the infusion study were similar in the two groups (51 +/- 2 v 56 +/- 2 microU/mL), the SSPG concentrations were significantly higher (P < .02) in those who developed preeclampsia (160 +/- 17 v 119 +/- 17 mg/dL). Thus, when studied 2 months after delivery, women who developed preeclampsia were relatively insulin resistant and hyperinsulinemic when compared to those who had an uncomplicated pregnancy.

Insulin resistance, glucose intolerance, and hyperinsulinemia. Hypertriglyceridemia versus hypercholesterolemia.

Plasma glucose and insulin responses to oral glucose and mixed meals and the ability of insulin to stimulate glucose disposal were quantified in normal volunteer subjects and patients with types IIA, IIB, and IV hyperlipoproteinemia (HLP). The results indicated that patients with either type IIB or IV HLP had higher plasma glucose (p < 0.05-< 0.001) and insulin (p < 0.001) responses to both oral glucose and mixed meals compared with the normal subjects and patients with type IIA HLP. Steady-state plasma glucose concentrations (mmol/L) were also higher (p < 0.001) in patients with types IIB (13.3 +/- 0.6) and IV (12.8 +/- 1.2) HLP during a continuous infusion of somatostatin, glucose, and insulin than either the control group (volunteer subjects) (6.2 +/- 0.9) or patients with type IIA HLP (5.6 +/- 1.0). Because the steady-state plasma insulin concentrations were similar in all four groups, patients with either type IIB or IV HLP were resistant to insulin-mediated glucose uptake. These data indicate that patients with hypertriglyceridemia are insulin resistant, glucose intolerant, and hyperinsulinemic, irrespective of the plasma cholesterol concentration. The results further demonstrate that hypercholesterolemic patients with normal triglyceride concentrations do not have any abnormalities of glucose and insulin metabolism.

Insulin resistance, glucose intolerance, and hyperinsulinemia in patients with microvascular angina

Plasma glucose and insulin responses to oral glucose and insulin-mediated glucose disposal were determined in 20 patients with microvascular angina and 20 normal volunteers who were similar in terms of age, gender distribution, and degree of obesity. Plasma glucose and insulin responses to a 75-g oral glucose challenge were significantly higher in those with microvascular angina (P < .001), as were steady-state plasma glucose concentrations after a 180-minute infusion of somatostatin, glucose, and insulin (12.2 +/- 1.0 v 7.6 +/- 0.6 mmol/L, P < .001). Since steady-state plasma insulin concentrations were similar in the two groups (627 +/- 32 v 631 +/- 29 pmol/L), these data indicate that patients with microvascular angina are insulin-resistant, glucose-intolerant, and hyperinsulinemic compared with a matched group of normal volunteers.

Effect of pravastatin treatment on glucose, insulin, and lipoprotein metabolism in patients with hypercholesterolemia

Treatment of patients with type IIA hyperlipoproteinemia (HLP) with pravastatin for 3 months led to significant decreases (p < 0.001) in total cholesterol (7.18 +/- 0.30 to 5.75 +/- 0.30 mmol/L), LDL cholesterol (5.56 +/- 0.33 to 4.02 +/- 0.32 mmol/L), and ratio of total cholesterol to HDL cholesterol (6.5 +/- 0.4 to 4.6 +/- 0.4). Decreases of a similar magnitude were also seen in patients with type IIB HLP. Plasma glucose and insulin concentrations after an oral glucose load and from 8 AM to 4PM in response to meals were higher in patients with Type IIB HLP, who also had higher steady-state plasma glucose concentrations after an infusion of somatostatin, insulin, and glucose (12.4 +/- 1 vs 5.5 +/- 0.8 mmol/L, p < 0.001). Because steady-state plasma insulin concentrations were similar in both groups, patients with type IIB HLP were relatively insulin resistant. Furthermore, day-long plasma glucose concentrations and insulin resistance were modestly, but significantly (p < 0.01), greater after treatment in both groups. In conclusion, LDL cholesterol metabolism improved in hypercholesterolemic subjects treated with pravastatin, but the hypertriglyceridemia, insulin resistance, relative glucose intolerance, and hyperinsulinemia present in patients with type IIB HLP either did not improve with treatment or was somewhat worse.

Impact of Lifestyle-Related Factors on All-Cause and Cause-Specific Mortality in Patients With Type 2 Diabetes: The Taichung Diabetes Study

OBJECTIVE To examine whether combined lifestyle behaviors have an impact on all-cause and cause-specific mortality in patients aged 30–94 years with type 2 diabetes (T2DM). RESEARCH DESIGN AND METHODS Participants included 5,686 patients >30 years old with T2DM who were enrolled in a Diabetes Care Management Program at a medical center in central Taiwan before 2007. Lifestyle behaviors consisted of smoking, alcohol drinking, physical inactivity, and carbohydrate intake. The main outcomes were all-cause and cause-specific mortality. Cox proportional hazards models were used to examine the association between combined lifestyle behaviors and mortality. RESULTS The mortality rate among men was 24.10 per 1,000 person-years, and that among women was 17.25 per 1,000 person-years. After adjusting for the traditional risk factors, we found that combined lifestyle behavior was independently associated with all-cause mortality and mortality due to diabetes, cardiovascular disease, and cancer. Patients with three or more points were at a 3.50-fold greater risk of all-cause mortality (95% CI 2.06–5.96) and a 4.94-fold (1.62–15.06), 4.24-fold (1.20–14.95), and 1.31-fold (0.39–4.41) greater risk of diabetes-specific, CVD-specific, and cancer-specific mortality, respectively, compared with patients with zero points. Among these associations, the combined lifestyle behavior was not significantly associated with cancer mortality. CONCLUSIONS Combined lifestyle behavior is a strong predictor of all-cause and cause-specific mortality in patients with T2DM.

Causes of death and associated factors among patients with non-insulin- dependent diabetes mellitus in Taipei, Taiwan

A cohort of 766 patients with non-insulin-dependent diabetes mellitus (NIDDM) from a general teaching hospital in Taipei, Taiwan were followed prospectively to assess survival experience and associated risk factors. Data were abstracted from the medical records and additional information was obtained from patients or their closest relatives using a structured questionnaire. Date and cause of death were determined from death certificates. Standardized mortality ratios were calculated by the direct method. Chi2-Square test and Coxs proportional hazard analysis were used to control for potential confounders. During a median follow-up of 3.5 years (range 1 month to 4.6 years), 131 deaths occurred. Of these, 29.8% were due to cardiopulmonary disease (ICD 401-429), 13.0% due to cerebrovascular disease (ICD 430-438), 13.0% due to acute diabetes metabolic complications (250.1, 250.2), and 11.4% due to nephropathy (580-589). Adjusted for age, people with NIDDM had 2.2 (95% CI 1.6-2.9) times the risk of death than members of the general population, and cause-specific standardized mortality ratios were: CPD 4.6, nephropathy 8.8, cerebrovascular disease 1.9, and neoplasm 0.7. Age, fasting plasma glucose, hypertension, and proteinuria were positively and independently associated with all-cause mortality (P < 0.05 for each). Thus, NIDDM patients have higher mortality rates than the general population in Taiwan, and age, fasting plasma glucose, hypertension, and proteinuria are associated with this excess risk. Proper application of available interventions may control these factors with a consequent reduction in mortality. Particular attention is needed to prevent deaths from the acute metabolic complications of diabetes.

Prospective evaluation of insulin resistance and lipid metabolism in women receiving oral contraceptives.

OBJECTIVES It has been suggested that normal women receiving oral contraceptives (OC) may develop a series of metabolic side‐effects which relate to the risk of cardiovascular disease. These metabolic disturbances include changes in glucose and insulin metabolism, raised serum lipid and lipoprotein concentrations and elevated blood pressure. All these changes indicate that OC might cause insulin resistance. We have prospectively examined the effect of OC on insulin resistance and lipid metabolism including Lp(a) values.

Effect of Glipizide Treatment on Response to an Infused Glucose Load in Patients With NIDDM

OBJECTIVE This study was initiated to compare the effect of sulfonylurea treatment on the response to an infused glucose load of patients with non-insulin-dependent diabetes mellitus (NIDDM) at a basal insulin concentration and in response to physiological hyperinsulinemia. RESEARCH DESIGN AND METHODS We used the insulin suppression test, in which subjects were infused for 180 min with somatostatin, exogenous insulin, and glucose. Since similar steady-state plasma insulin (SSPI) concentrations are reached in all subjects, the resultant steady-state plasma glucose (SSPG) concentration permits comparison of the ability of a given individual to maintain glucose homeostasis in response to the infused glucose load. RESULTS We studied 15 nonobese patients at two different SSPI concentrations, before and after glipizide treatment, at basal (68 ± 4 pmol/l) and high (470 ± 31 pmol/l) levels. Values for SSPG concentrations were lower after treatment at both the basal (15.3 ± 0.5 vs. 18.5 ± 0.6 mmol/l; P < 0.001) and the high (10.6 ± 0.7 vs. 14.2 ± 0.7 mmol/l; P < 0.001) SSPI concentrations. To compare the responses of each patient before and after treatment, we calculated the fractional glucose metabolic rate, i.e., (glucose infusion rate — urinary glucose loss) ÷ by SSPG. To provide an alternative method of comparing the effect of sulfonylurea treatment, we divided the incremental increase in fractional metabolic glucose rate between the studies done at the low and high SSPI by the incremental increase in SSPI between the two studies (insulin sensitivity index [S1]). CONCLUSIONS The results of these calculations indicated that glipizide treatment was associated with a significant increase in fractional glucose metabolic rate at a basal insulin concentration (29 ± 3 to 42 ± 2 ml · m−2 · min−1, P < 0.001), and in response to the incremental change in SSPI (14 ± 4 to 23 ± 3 ml · m−2 · min−1, P < 0.02). Finally, S1 also increased in association with sulfonylurea (0.24 ± 0.06 to 0.43 ± 0.07 ml · m−2 · min−1/μU · ml−1, P < 0.001).

Hepatic Insulin Extraction and Insulin Clearance in Patients with Essential Hypertension

To understand the mechanism of hyperinsulinemia in patients with high blood pressure, we studied 20 untreated essential hypertensives and 20 age, sex and body mass index-matched normotensive control subjects. C-peptide concentrations and C-peptide to insulin molar ratio in response to a 75 g oral glucose challenge were used to evaluate the beta cells function and for calculation of hepatic extraction of insulin. Modified insulin suppression test was employed to compared the insulin-stimulated glucose uptake and insulin clearance rate between two groups. Patients with hypertension had significantly higher plasma glucose, insulin and C-peptide responses as compared to normal subjects (P < 0.05, p < 0.01, and P < 0.03, respectively). Mean steady state plasma glucose (SSPG) concentrations were also higher in hypertensive group than normotensive group (11.5 +/- 1.4 vs 6.7 +/- 0.9 mmol/L, p < 0.01) despite that mean steady state plasma insulin (SSPI) values were relatively similar, indicating the presence of insulin resistance. Hepatic insulin extraction was found to be elevated in patients with high blood pressure when compared to normal subjects (82 +/- 3 vs 72 +/- 2%, p < 0.05). However, there were no difference in insulin clearance rate between two groups (592 +/- 38 vs 559 +/- 40 mL/m2/min, p = NS). In conclusion, hyperinsulinemia in patients with hypertension result from hypersecretion of beta cells and increased hepatic extraction of insulin. No difference was found in insulin clearance rate between hypertensive and normotensive subjects.