Manisha Chandalia

Beneficial Effects of High Dietary Fiber Intake in Patients with Type 2 Diabetes Mellitus

BACKGROUND The effect of increasing the intake of dietary fiber on glycemic control in patients with type 2 diabetes mellitus is controversial. METHODS In a randomized, crossover study, we assigned 13 patients with type 2 diabetes mellitus to follow two diets, each for six weeks: a diet containing moderate amounts of fiber (total, 24 g; 8 g of soluble fiber and 16 g of insoluble fiber), as recommended by the American Diabetes Association (ADA), and a high-fiber diet (total, 50 g; 25 g of soluble fiber and 25 g of insoluble fiber), containing foods not fortified with fiber (unfortified foods). Both diets, prepared in a research kitchen, had the same macronutrient and energy content. We compared the effects of the two diets on glycemic control and plasma lipid concentrations. RESULTS Compliance with the diets was excellent. During the sixth week, the high-fiber diet, as compared with the the sixth week of the ADA diet, mean daily preprandial plasma glucose concentrations were 13 mg per deciliter [0.7 mmol per liter] lower (95 percent confidence interval, 1 to 24 mg per deciliter [0.1 to 1.3 mmol per liter]; P=0.04) and mean median difference, daily urinary glucose excretion 1.3 g (0.23; 95 percent confidence interval, 0.03 to 1.83 g; P= 0.008). The high-fiber diet also lowered the area under the curve for 24-hour plasma glucose and insulin concentrations, which were measured every two hours, by 10 percent (P=0.02) and 12 percent (P=0.05), respectively. The high-fiber diet reduced plasma total cholesterol concentrations by 6.7 percent (P=0.02), triglyceride concentrations by 10.2 percent (P=0.02), and very-low-density lipoprotein cholesterol concentrations by 12.5 percent (P=0.01). CONCLUSIONS A high intake of dietary fiber, particularly of the soluble type, above the level recommended by the ADA, improves glycemic control, decreases hyperinsulinemia, and lowers plasma lipid concentrations in patients with type 2 diabetes.

Metabolic Dysregulation and Adipose Tissue Fibrosis: Role of Collagen VI†

ABSTRACT Adipocytes are embedded in a unique extracellular matrix whose main function is to provide mechanical support, in addition to participating in a variety of signaling events. During adipose tissue expansion, the extracellular matrix requires remodeling to accommodate adipocyte growth. Here, we demonstrate a general upregulation of several extracellular matrix components in adipose tissue in the diabetic state, therefore implicating “adipose tissue fibrosis” as a hallmark of metabolically challenged adipocytes. Collagen VI is a highly enriched extracellular matrix component of adipose tissue. The absence of collagen VI results in the uninhibited expansion of individual adipocytes and is paradoxically associated with substantial improvements in whole-body energy homeostasis, both with high-fat diet exposure and in the ob/ob background. Collectively, our data suggest that weakening the extracellular scaffold of adipocytes enables their stress-free expansion during states of positive energy balance, which is consequently associated with an improved inflammatory profile. Therefore, the disproportionate accumulation of extracellular matrix components in adipose tissue may not be merely an epiphenomenon of metabolically challenging conditions but may also directly contribute to a failure to expand adipose tissue mass during states of excess caloric intake.

Insulin Resistance and Body Fat Distribution in South Asian Men Compared to Caucasian Men

Objective South Asians are susceptible to insulin resistance even without obesity. We examined the characteristics of body fat content, distribution and function in South Asian men and their relationships to insulin resistance compared to Caucasians. Research Design and Methods Twenty-nine South Asian and 18 Caucasian non-diabetic men (age 27±3 and 27±3 years, respectively) underwent euglycemic-hyperinsulinemic clamp for insulin sensitivity, underwater weighing for total body fat, MRI of entire abdomen for intraperitoneal (IP) and subcutaneous abdominal (SA) fat and biopsy of SA fat for adipocyte size. Results Compared to Caucasians, in spite of similar BMI, South Asians had higher total body fat (22±6 and 15±4% of body weight; p-value<0.0001), higher SA fat (3.5±1.9 and 2.2±1.3 kg, respectively; p-value = 0.004), but no differences in IP fat (1.0±0.5 and 1.0±0.7 kg, respectively; p-value = 0.4). SA adipocyte cell size was significantly higher in South Asians (3491±1393 and 1648±864 µm2; p-value = 0.0001) and was inversely correlated with both glucose disposal rate (r-value = −0.57; p-value = 0.0008) and plasma adiponectin concentrations (r-value = −0.71; p-value<0.0001). Adipocyte size differences persisted even when SA was matched between South Asians and Caucasians. Conclusions Insulin resistance in young South Asian men can be observed even without increase in IP fat mass and is related to large SA adipocytes size. Hence ethnic excess in insulin resistance in South Asians appears to be related more to excess truncal fat and dysfunctional adipose tissue than to excess visceral fat.

Ethnicity and type 2 diabetes: Focus on Asian Indians

Though the overall prevalence of type 2 diabetes is increasing in US and in all other westernized countries, significant differences are noted among different ethnic groups. The reasons for ethnic differences in the risk of type 2 diabetes are not entirely understood. For example, Asian Indians (people from India, Pakistan, and Bangladesh) have remarkably high prevalence of type 2 diabetes compared to Caucasians. However, the incidence of obesity, an important risk factor in the development of type 2 diabetes, is significantly lower in Asian Indians compared to Caucasians. Though westernization of lifestyle with dietary changes and lack of exercise may play a role in increased prevalence of type 2 diabetes in migrant Asian Indians, various epidemiological studies have shown that these factors alone are not sufficient to explain this trend. One important factor contributing to increased type 2 diabetes in Asian Indians is excessive insulin resistance compared to Caucasians. This difference in the degree of insulin resistance may be explained by either an environmental or a genetic factor or by combination of both. The understanding of the etiology and mechanisms causing increased insulin resistance in Asian Indians will provide clues to more effective prevention and treatment of diabetes in this ethnic group. Furthermore, the information may help in understanding the pathophysiology of type 2 diabetes in other ethnic groups and improve methods of treatment and prevention in all ethnic groups. Since the ethnic mix of the US population is changing rapidly and it is estimated that by the year 2020, over 50% of US population will include non-Caucasian ethnicity, the identification of the mechanism involved in the excessive development of type 2 diabetes in non-Caucasians becomes important. In this review, possible etiology of excessive insulin resistance and role of free fatty acids (FFA) in insulin resistance in Asian Indians is discussed. Finally, the role of targeting insulin resistance in prevention and treatment of diabetes is discussed.

Diet composition and the metabolic syndrome: what is the optimal fat intake?

Two cholesterol-raising fatty acids in the diet, saturated fatty acids and trans fatty acids, increase the serum low-density lipoprotein cholesterol concentration. This fact justifies the recommendation of a reduced intake of cholesterol-raising fatty acids. Emerging data suggest that diets higher in unsaturated fatty acids, particularly monounsaturated fatty acids, have several advantages over high-carbohydrate intakes. This advantage appears to hold, particularly for populations having a high prevalence of insulin resistance, such as the US population. If the US public were to modify its eating habits in the direction of better weight control and more exercise, higher intakes of carbohydrate might be better tolerated. At the same time, the experience with the Mediterranean population reveals that in healthier populations, diets relatively high in unsaturated fatty acids are well tolerated and are associated with a low prevalence of both coronary heart disease and type 2 diabetes.

Metabolic correlates of nonalcoholic fatty liver in women and men

Nonalcoholic hepatic steatosis associates with a clustering of metabolic risk factors and steatohepatitis. One risk factor for hepatic steatosis is obesity, but other factors likely play a role. We examined metabolic concomitants of hepatic steatosis in nonobese and obese men and women. Sixty‐one obese women and 35 obese men were studied; both those with and without hepatic steatosis were compared against each other and against nonobese controls (17 women and 32 men) without hepatic steatosis. Obesity (defined as ≥25% body fat in men and ≥35% in women), was identified by x‐ray absorptiometry, whereas hepatic steatosis (≥5.5% liver fat) was detected by magnetic resonance spectroscopy. The primary endpoint was a difference in insulin sensitivity. Obese groups with and without steatosis had similar body fat percentages. Compared with obese women without hepatic steatosis, those with steatosis were more insulin resistant; the same was true for men, although differences were less striking. Obese subjects with hepatic steatosis had higher ratios of truncal‐to‐lower body fat and other indicators of adipose tissue dysfunction compared with obese subjects without steatosis. Conclusion: These results support the concept that obesity predisposes to hepatic steatosis; but in addition, insulin resistance beyond that induced by obesity alone and a relatively high ratio of truncal‐to‐lower body fat usually combined with obesity to produce an elevated liver fat content. (HEPATOLOGY 2007.)

Role of Genetic Polymorphism Peroxisome Proliferator–Activated Receptor-γ2 Pro12Ala on Ethnic Susceptibility to Diabetes in South-Asian and Caucasian Subjects

OBJECTIVE—To determine whether the peroxisome proliferator–activated receptor (PPAR)-γ Pro12ala polymorphism modulates susceptibility to diabetes in South Asians. RESEARCH DESIGN AND METHODS—South Asians (n = 697) and Caucasians (n = 457) living in Dallas/Forth Worth, Texas, and South Asians living in Chennai, India (n = 1,619), were enrolled for this study. PPAR-γ Pro12Ala was determined using restriction fragment–length polymorphism. Insulin responsiveness to an oral glucose tolerance test (OGTT) was measured in nondiabetic subjects. RESULTS—The Caucasian diabetic subjects had significantly lower prevalence of PPAR-γ 12Ala when compared with the Caucasian nondiabetic subjects (20 vs. 9%, P = 0.006). However, there were no significant differences between diabetic and nondiabetic subjects with reference to the Pro12Ala polymorphism among the South Asians living in Dallas (20 vs. 23%) and in India (19 vs. 19.3%). Although Caucasians carrying PPAR-γ Pro12Ala had lower plasma insulin levels at 2 h of OGTT than the wild-type (Pro/Pro) carriers (76 ± 68 and 54 ± 33 μU/ml, respectively, P = 0.01), no differences in either fasting or 2-h plasma insulin concentrations were found between South Asians carrying the PPAR-γ Pro12Ala polymorphism and those with the wild-type genotype at either Chennai or Dallas. CONCLUSIONS—Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that the PPAR-γ Pro12Ala polymorphism is protective against diabetes in Caucasians but not in South Asians.

Indices of Cholesterol Metabolism and Relative Responsiveness to Ezetimibe and Simvastatin

CONTEXT The level and duration of exposure to circulating low-density lipoprotein-cholesterol (LDL-C) are major contributors to coronary atherosclerosis. Therefore, optimal prevention will require long-term LDL-C reduction, making it important to select the most effective agent for each individual. OBJECTIVE We tested the hypothesis that individuals with high fractional absorption of cholesterol respond better to the cholesterol absorption inhibitor ezetimibe than to simvastatin, whereas low absorbers, who have elevated rates of cholesterol synthesis, respond better to simvastatin. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled, crossover trial was performed in 215 African- and European-American men. INTERVENTION Participants were randomized to placebo, ezetimibe (10 mg/d), simvastatin (10 mg/d), and both drugs for 6 wk each. MAIN OUTCOME Plasma levels of LDL-C, surrogate markers for cholesterol absorption (campesterol) and synthesis (lathosterol), and proprotein convertase subtilisin-like kexin type 9 were measured at baseline and after treatment. RESULTS LDL-C levels were reduced by 19% (ezetimibe), 25% (simvastatin), and 41% (ezetimibe+simvastatin) from a baseline of 146 +/- 20 mg/dl; results were similar between ethnic groups. Reduction in LDL-C correlated poorly with baseline levels of noncholesterol sterols and proprotein convertase subtilisin-like kexin type 9. Although individual responses varied widely, change in LDL-C on ezetimibe correlated with response to simvastatin (r = 0.46, P < 0.001). Combination therapy lowered LDL-C by 15% or greater in more than 95% of participants. CONCLUSIONS Baseline cholesterol absorption and synthesis did not predict responsiveness to LDL-lowering drugs. Responsiveness to simvastatin and ezetimibe were highly correlated, suggesting that factors downstream of the primary sites of action of these drugs are a major determinant of response.

Screening and biochemical analysis of GATA4 sequence variations identified in patients with congenital heart disease

Few known monogenic causes of non‐syndromic congenital heart disease (CHD) have been identified. Mutations in NKX2.5 were initially implicated in familial cases of cardiac septal defects and subsequently, functionally significant NKX2.5 mutations were found in diverse forms of non‐syndromic CHD. Similarly, mutations in GATA4, which encodes a cardiac transcription factor, were first identified in familial cases of cardiac septal defects. We hypothesize that individuals with non‐syndromic CHD may harbor GATA4 mutations and that these mutations alter the biochemical properties of the protein. The coding region encompassing the six exons of GATA4 was screened in a study population of 157 patients with CHD. We identified several sequence variations in GATA4. We tested these novel sequence variations that altered evolutionarily conserved amino acids and other previously reported GATA4 mutations in various biochemical assays. The novel sequence variations had no biochemical deficits while a previously reported, but unstudied, missense mutation in GATA4 (S52F) functioned as a hypomorph in transactivation assays. We did not identify any novel GATA4 mutations in our patient population with non‐syndromic CHD. Consistent with previous findings, GATA4 mutations that result in deficits in transactivation ability are consistently associated with CHD suggesting that normal transactivation properties of GATA4 are required for proper cardiac development.

The TRIB3 Q84R polymorphism and risk of early-onset type 2 diabetes

CONTEXT The prevalence of type 2 diabetes (T2D), particularly among young adults, has been rising steadily during the past 2 decades. T2D, especially in its early-onset subtype, is under genetic control. TRIB3 inhibits insulin-stimulated Akt phosphorylation and subsequent insulin action. A TRIB3 gain-of-function polymorphism, Q84R (rs2295490), impairs insulin signaling. OBJECTIVE The objective of the study was to verify the association of TRIB3 Q84R with: 1) T2D, either subtyped or not according to age at diagnosis (early-onset, <45 yr, or >or= 45 yr); 2) insulin secretion and sensitivity in nondiabetic individuals; or 3) in vitro insulin secretion from isolated human islets. DESIGN Four different case-control samples comprising a total of 5,469 whites were examined. Insulinogenic and insulin sensitivity indexes and their interplay (disposition index) were assessed in 645 nondiabetic individuals at oral glucose tolerance test, glucose (16.7 mmol/liter)-induced in vitro insulin secretion was assessed in islets isolated from 54 nondiabetic donors. RESULTS In the whole sample, the R84 variant was nominally associated with T2D (odds ratio 1.17, 95% confidence interval 1.00-1.36, P = 0.04). When stratifying according to age of diabetes onset, R84 carriers had an increased risk of early-onset T2D (odds ratio 1.32, 95% confidence interval 1.10-1.58, P = 0.002). Among 645 nondiabetic subjects, R84 carriers had higher glucose levels (P = 0.005) and lower insulinogenic (P = 0.03) and disposition index (P = 0.02) during the oral glucose tolerance test. R84 islets were more likely to display relatively low glucose-stimulated insulin release (P = 0.04). CONCLUSIONS The TRIB3 R84 variant is associated with early-onset T2D in whites. Alteration in the insulin secretion/insulin sensitivity interplay appears to underlie this association.