Obesity and insulin resistance are associated with the development of type 2 diabetes. It is well accepted that beta cell dysfunction is required for hyperglycaemia to occur. The prevailing view is ...that, in the presence of insulin resistance, beta cell dysfunction that occurs early in the course of the disease process is the critical abnormality. An alternative model has been proposed in which primary beta cell overstimulation results in insulin hypersecretion that then leads to the development of obesity and insulin resistance, and ultimately to beta cell exhaustion. In this review, data from preclinical and clinical studies, including intervention studies, are discussed in the context of these models. The preponderance of the data supports the view that an early beta cell functional defect is the more likely mechanism underlying the pathogenesis of hyperglycaemia in the majority of individuals who develop type 2 diabetes.
Graphical abstract
Context:
Type 2 diabetes mellitus is associated with gastrointestinal dysbiosis involving both compositional and functional changes in the gut microbiome. Changes in diet and supplementation with ...probiotics and prebiotics (ie, fermentable fibers) can induce favorable changes in gut bacterial species and improve glucose homeostasis.
Objective:
This paper will review the data supporting several potential mechanisms whereby gut dysbiosis contributes to metabolic dysfunction, including microbiota driven increases in systemic lipopolysaccharide concentrations, changes in bile acid metabolism, alterations in short chain fatty acid production, alterations in gut hormone secretion, and changes in circulating branched-chain amino acids.
Methods:
Data for this review were identified by searching English language references from PubMed and relevant articles.
Conclusions:
Understanding the mechanisms linking the gut microbiome to glucose metabolism, and the relevant compositional and functional characteristics of the gut microbiome, will help direct future research to develop more targeted approaches or novel compounds aimed at restoring a more healthy gut microbiome as a new approach to prevent and treat type 2 diabetes mellitus and related metabolic conditions.
This review details potential mechanisms linking gut dysbiosis to metabolic dysfunction, including lipopolysaccharide, bile acids, short chain fatty acids, gut hormones, and branched-chain amino acids.
Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes. In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, ...glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance. When insulin resistance is accompanied by dysfunction of pancreatic islet β-cells - the cells that release insulin - failure to control blood glucose levels results. Abnormalities in β-cell function are therefore critical in defining the risk and development of type 2 diabetes. This knowledge is fostering exploration of the molecular and genetic basis of the disease and new approaches to its treatment and prevention.
Insulin resistance is an almost universal finding in nonalcoholic fatty liver disease (NAFLD). This review outlines the evidence linking insulin resistance and NAFLD, explores whether liver fat is a ...cause or consequence of insulin resistance, and reviews the current evidence for treatment of NAFLD.
Evidence from epidemiological, experimental, and clinical research studies investigating NAFLD and insulin resistance was reviewed.
Insulin resistance in NAFLD is characterized by reductions in whole-body, hepatic, and adipose tissue insulin sensitivity. The mechanisms underlying the accumulation of fat in the liver may include excess dietary fat, increased delivery of free fatty acids to the liver, inadequate fatty acid oxidation, and increased de novo lipogenesis. Insulin resistance may enhance hepatic fat accumulation by increasing free fatty acid delivery and by the effect of hyperinsulinemia to stimulate anabolic processes. The impact of weight loss, metformin, and thiazolidinediones, all treatments aimed at improving insulin sensitivity, as well as other agents such as vitamin E, have been evaluated in patients with NAFLD and have shown some benefit. However, most intervention studies have been small and uncontrolled.
Insulin resistance is a major feature of NAFLD that, in some patients, can progress to steatohepatitis. Treatments aimed at reducing insulin resistance have had some success, but larger placebo-controlled studies are needed to fully establish the efficacy of these interventions and possibly others in reducing the deleterious effects of fat accumulation in the liver.
Abstract
Context
Total insulin clearance is decreased in nonalcoholic fatty liver disease (NAFLD), but the relationship between liver fat and hepatic insulin extraction (HIE) is unknown.
Objective
...This cross-sectional study addresses the hypothesis that HIE is reduced in NAFLD and investigates metabolic and/or anthropometric characteristics most closely associated with insulin clearance.
Participants
Nondiabetic subjects with NAFLD (n = 13) and age- and body mass index (BMI)-matched controls with normal liver enzymes (n = 15) underwent abdominal CT, dual-energy X-ray absorptiometry, oral glucose tolerance test (OGTT), and labeled two-step hyperinsulinemic-euglycemic clamps.
Outcome Measurements
Liver fat was estimated by the CT liver/spleen ratio. Hepatic and extrahepatic insulin clearances were modeled using clamp and OGTT data.
Results
Extrahepatic insulin clearance and HIE were not different between NAFLD and controls and did not correlate with liver fat. HIE was positively correlated with insulin sensitivity rate of glucose disposal (Rd; low r = +0.7, P < 0.001; high r = +0.6, P = 0.001), adiponectin (r = +0.55, P = 0.004), and insulin-mediated suppression of clamp nonesterified free fatty acid (NEFA; r = +0.67, P < 0.001) but was not associated with fasting NEFA, insulin-mediated suppression of glucose production, or measures of adiposity. Extrahepatic insulin clearance was positively associated with percent body fat (r = +0.44, P = 0.02) and subcutaneous fat (r = +0.42, P = 0.03) but not BMI, intra-abdominal fat, liver fat, Rd, adiponectin, or NEFA.
Conclusions
HIE is not directly associated with hepatic steatosis but is associated with muscle and adipose tissue insulin resistance. The data suggest differential regulation of insulin clearance with extrahepatic insulin clearance being associated with body fat and not insulin sensitivity.
Modeling of clamp and oral glucose tolerance test data revealed that hepatic insulin extraction is not directly associated with hepatic steatosis but is associated with muscle and adipose tissue insulin sensitivity.
Background and Aim
The metabolic syndrome (MetS) and each of its components are strongly associated with non‐alcoholic fatty liver disease (NAFLD). This has led many investigators to suggest that ...NAFLD is an independent component of the MetS. We formally tested this hypothesis using confirmatory factor analysis, which allows comparison of different models, with or without including NAFLD as a component of the MetS.
Methods
We analyzed data from 3846 subjects of the Third National Health and Nutrition Examination Survey (1988–1994). NAFLD was defined by increased liver fat measured by ultrasonography.
Results
MetS by Adult Treatment Panel III criteria was present in 20.5%, and 30.2% had NAFLD, defined as mild, moderate, or severe ultrasonographic steatosis. Using confirmatory factor analysis, a basic model representing the MetS using its currently accepted components (glucose, waist, triglyceride/high‐density lipoprotein ratio, and mean arterial pressure) showed excellent goodness‐of‐fit statistics. Addition of NAFLD to the model as a fifth independent variable decreased model fit, suggesting that NAFLD is not an additional independent component of the MetS. Analysis by ethnicity showed that addition of NAFLD decreased model fit in Whites but resulted in minor improvements in non‐Hispanic Blacks and Mexican Americans.
Conclusions
The MetS is strongly associated with NAFLD. However, we found no evidence that NAFLD is an independent component or manifestation of the MetS. Interestingly, ethnic differences might be important in this relationship and require further study.
OBJECTIVE:--We sought to determine whether an oral disposition index (DIO) predicts the development of diabetes over a 10-year period. First, we assessed the validity of the DIO by demonstrating that ...a hyperbolic relationship exists between oral indexes of insulin sensitivity and β-cell function. RESEARCH DESIGN AND METHODS--A total of 613 Japanese-American subjects (322 men and 291 women) underwent a 75-g oral glucose tolerance test (OGTT) at baseline, 5 years, and 10 years. Insulin sensitivity was estimated as 1/fasting insulin or homeostasis model assessment of insulin sensitivity (HOMA-S). Insulin response was estimated as the change in insulin divided by change in glucose from 0 to 30 min (ΔI₀₋₃₀/ΔG₀₋₃₀). RESULTS:--ΔI₀₋₃₀/ΔG₀₋₃₀ demonstrated a curvilinear relationship with 1/fasting insulin and HOMA-S with a left and downward shift as glucose tolerance deteriorated. The confidence limits for the slope of the loge-transformed estimates included -1 for ΔI₀₋₃₀/ΔG₀₋₃₀ versus 1/fasting insulin for all glucose tolerance groups, consistent with a hyperbolic relationship. When HOMA-S was used as the insulin sensitivity measure, the confidence limits for the slope included -1 only for subjects with normal glucose tolerance (NGT) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) but not diabetes. On the basis of this hyperbolic relationship, the product of ΔI₀₋₃₀/ΔG₀₋₃₀ and 1/fasting insulin was calculated (DIO) and decreased from NGT to IFG/IGT to diabetes (P < 0.001). Among nondiabetic subjects at baseline, baseline DIO predicted cumulative diabetes at 10 years (P < 0.001) independent of age, sex, BMI, family history of diabetes, and baseline fasting and 2-h glucose concentrations. CONCLUSIONS:--The DIO provides a measure of β-cell function adjusted for insulin sensitivity and is predictive of development of diabetes over 10 years.
Adiponectin is an adipocyte-specific secretory protein that circulates in serum as a hexamer of relatively low molecular weight (LMW) and a larger multimeric structure of high molecular weight (HMW). ...Serum levels of the protein correlate with systemic insulin sensitivity. The full-length protein affects hepatic gluconeogenesis through improved insulin sensitivity, and a proteolytic fragment of adiponectin stimulates β oxidation in muscle. Here, we show that the ratio, and not the absolute amounts, between these two oligomeric forms (HMW to LMW) is critical in determining insulin sensitivity. We define a new index, SA, that can be calculated as the ratio of HMW/(HMW + LMW). db/db mice, despite similar total adiponectin levels, display decreased SA values compared with wild type littermates, as do type II diabetic patients compared with insulin-sensitive individuals. Furthermore, SA improves with peroxisome proliferator-activated receptor-γ agonist treatment (thiazolidinedione; TZD) in mice and humans. We demonstrate that changes in SA in a number of type 2 diabetic cohorts serve as a quantitative indicator of improvements in insulin sensitivity obtained during TZD treatment, whereas changes in total serum adiponectin levels do not correlate well at the individual level. Acute alterations in SA (ΔSA) are strongly correlated with improvements in hepatic insulin sensitivity and are less relevant as an indicator of improved muscle insulin sensitivity in response to TZD treatment, further underscoring the conclusions from previous clamp studies that suggested that the liver is the primary site of action for the full-length protein. These observations suggest that the HMW adiponectin complex is the active form of this protein, which we directly demonstrate in vivo by its ability to depress serum glucose levels in a dose-dependent manner.
Intra-Abdominal Fat Is a Major Determinant of the National Cholesterol Education Program Adult Treatment Panel III Criteria
for the Metabolic Syndrome
Darcy B. Carr 1 ,
Kristina M. Utzschneider 2 ,
...Rebecca L. Hull 2 ,
Keiichi Kodama 2 ,
Barbara M. Retzlaff 2 ,
John D. Brunzell 2 ,
Jane B. Shofer 3 ,
Brian E. Fish 2 ,
Robert H. Knopp 2 and
Steven E. Kahn 2
1 Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington
2 Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, Veterans Affairs Puget Sound Health Care System
and Harborview Medical Center, University of Washington, Seattle, Washington
3 Department of Rehabilitation Research and Development, University of Washington, Seattle, Washington
Address correspondence and reprint requests to Darcy B. Carr, MD, Assistant Professor, Box 356460, Dept. OB/GYN, University
of Washington, Seattle, WA 98195-6460. E-mail: darcarr{at}u.washington.edu
Abstract
The underlying pathophysiology of the metabolic syndrome is the subject of debate, with both insulin resistance and obesity
considered as important factors. We evaluated the differential effects of insulin resistance and central body fat distribution
in determining the metabolic syndrome as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel
III. In addition, we determined which NCEP criteria were associated with insulin resistance and central adiposity. The subjects,
218 healthy men ( n = 89) and women ( n = 129) with a broad range of age (26–75 years) and BMI (18.4–46.8 kg/m 2 ), underwent quantification of the insulin sensitivity index ( S i ) and intra-abdominal fat (IAF) and subcutaneous fat (SCF) areas. The metabolic syndrome was present in 34 (15.6%) of subjects
who had a lower S i median: 3.13 vs. 6.09 × 10 −5 min −1 /(pmol/l) and higher IAF (166.3 vs. 79.1 cm 2 ) and SCF (285.1 vs. 179.8 cm 2 ) areas compared with subjects without the syndrome ( P < 0.001). Multivariate models including S i , IAF, and SCF demonstrated that each parameter was associated with the syndrome. However, IAF was independently associated
with all five of the metabolic syndrome criteria. In multivariable models containing the criteria as covariates, waist circumference
and triglyceride levels were independently associated with S i and IAF and SCF areas ( P < 0.001). Although insulin resistance and central body fat are both associated with the metabolic syndrome, IAF is independently
associated with all of the criteria, suggesting that it may have a pathophysiological role. Of the NCEP criteria, waist circumference
and triglycerides may best identify insulin resistance and visceral adiposity in individuals with a fasting plasma glucose
<6.4 mmol/l.
ATP III, Adult Treatment Panel III
BP, blood pressure
FPG, fasting plasma glucose
GEE, generalized estimating equation
IAF, intra-abdominal fat
NCEP, National Cholesterol Education Program
NHANES III, Third National Health and Nutrition Examination Survey
PAI-1, plasminogen activator inhibitor type 1
SCF, subcutaneous fat
TG, triglyceride
TNF-α, tumor necrosis factor-α
WC, waist circumference
Footnotes
Accepted May 17, 2004.
Received February 28, 2004.
DIABETES
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