Insulin Resistance and Hyperglycemia

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The WHO definition of the metabolic syndrome is the only one that utilizes a measure of insulin resistance as a required component, although elevated fasting glucose levels, specified by the ATP III and IDF definitions, are often associated with an insulin-resistant state. Insulin resistance can be defined as the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle, and liver cells. In mild cases of insulin resistance, increased insulin secretion by pancreatic P cells results in hyperinsulinemia to maintain eug-lycemia. As insulin resistance worsens, individuals whose increased pancreatic insulin secretion is unable to compensate for the reduced insulin action develop impaired glucose tolerance and hyperglycemia.

The "gold standard" for assessing insulin resistance is the euglycemic insulin clamp method (DeFronzo et al, 1979) and it remains the method to which all other tests of insulin sensitivity are compared. The method (Bergman et al, 1985; Del Prato s et al, 1985; Matsuda and DeFronzo , 1997) involves the administration of exogenous insulin to maintain a constant pre-set hyperinsulinemic level (typically 40-100 ^IU/ml). Simultaneously, the plasma glucose concentration is "clamped" at the norm fasting levels by means of an exogenous glucose infusion. Since plasma glucose concentrations are held constant, the glucose infusion rate equals glucose uptake by all the tissues in the body and reflects the tissue sensitivity to exogenous insulin. Technically, the method requires that two intravenous lines be inserted in the subject, one for insulin and glucose infusions and the other for frequent blood sampling to measure glucose levels. Glucose is measured at approximately 5-min intervals and glucose infusion rates are adjusted throughout the study to maintain euglycemia. Infusions are typically maintained for 2 h and insulin sensitivity (or its inverse insulin resistance) is determined from the average glucose infusion rate during the final 40 min when steady-state conditions are assumed. Insulin sensitivity can then be calculated by published methods (Bergman et al, 1985; Del Prato et al, 1985; Matsuda and DeFronzo, 1997).

Because the euglycemic clamp method is expensive, time consuming, and labor intensive, it is mainly used in research settings and is not practical for large population-based studies. Several modifications aimed at simplifying the method and other surrogate assessments have been proposed. The Minimal Model, as described by Bergmann and colleagues (Bergman et al, 1987; Finegood et al, 1984), requires only intravenous administration of glucose. It is less labor intensive than clamp techniques, yet still requires as many as 25 blood samples over 3 h and a computer-assisted mathematical analysis. A later refinement of the Minimal Model utilizes a simplified 12 blood sample method, but still requires intravenous access and 3 h to complete (Steil et al,

1993). The Minimal Model has correlated well with the euglycemic clamp over a broad range of insulin sensitivities (Finegood et al, 1984; Bergman et al, 1987); however, the correlation was reported to be lower in subjects with elevated levels of insulin resistance (Saad et al,

The oral glucose tolerance test (OGTT), routinely used for the diagnosis of impaired glucose tolerance (IGT) and diabetes, has been used to assess insulin sensitivity as well. Because no intravenous access is needed, OGTT is more practical for assessment of large populations. In this procedure one typically uses a 75 g glucose load in the form of a drink, and glucose and insulin are measured at various intervals over 2 h. Using a variable number of OGTT measurement time points, several mathematical models have been used to assess insulin resistance, and in general, these models have provided values that are significantly correlated with data generated from the euglycemic clamp (e.g., Bergman et al, 1987; Mari et al, 2001; Matsuda and DeFronzo, 1999). An advantage of OGTT-based indices is that they incorporate an assessment of insulin resistance in both the fasting and the postprandial phases.

Several models have been proposed to assess insulin sensitivity using fasting (home-ostatic) insulin and/or glucose levels (reviewed in Grundy, 1998a; Matthews et al, 1985a; Muniyappa et al, 2008). These measures assume that subjects are fasting and in a basal steady-state condition in which P-cell insulin secretion is relatively constant and glucose utilization matches glucose production. A limitation to all procedures that rely on insulin values is the lack of a standardized insulin assay (Sapin, 2007) which makes the results dependent on the assay chosen. Fasting serum insulin is a readily available measure, and elevated insulin levels can be indicative of insulin resistance; however, fasting insulin levels poorly correlate with insulin sensitivity as measured by the euglycemic clamp (Laakso, 1993).

The homeostasis model of insulin resistance (HOMA) (Matthews et al, 1985b) is calculated by the equation:

Homa = (Insulinfasting (^IU/ml)

(^IU/ml)xGlucosefastmg(mg/dl)/405)

The denominator of 405 (22.5 if glucose is expresses as mmol/l) is a normalizing factor obtained for a "normal healthy individual"

(fasting glucose 81 mg/dl and insulin 5 ^IU/ml). Variants of the HOMA calculation (e.g., log(HOMA) and 1/(HOMA)) have been shown to correlate better with euglycemic clamp results (Wallace et al, 2004). An alternative model, the quantitative insulin sensitivity check index (QUICKI) (Katz et al, 2000), utilizes log transformed fasting insulin and glucose values:

QUICKI = 1/ [log(InsulinfaSting) + log(GlucosefaSting)]

QUICKI was shown to provide a better linear correlation with the euglycemic clamp method than other surrogate measures, including HOMA, and is superior to the other fasting measures of insulin resistance (Chen et al, 2005; Ferrannini and Mari, 2004; Muniyappa et al, 2008; Pacini and Mari, 2003).

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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