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The Big Diabetes Lie

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FIGURE 1 The principal pathophysiological defects in type 2 diabetes mellitus. The solid line (bottom panel) shows that insulin resistance starts well before the onset of hyperglycemia and the diagnosis of diabetes. The dashed line in the bottom panel shows that the onset of diabetes is caused by failure of the compensatory hyperinsulinemia that characterizes the metabolic syndrome of insulin resistance, the precursor to diabetes or impaired glucose tolerance (IGT). In the top panel, the dotted line shows that post-meal glucose levels rise as insulin deficiency progresses and that only later does fasting glycemia deteriorate (solid line).

FIGURE 2 Based upon a homeostasis (HOMA) model, residual maximal insulin secretory reserve is depicted at the time of diagnosis and yearly for 6 years in subjects receiving diet only in the U.K. Prospective Diabetes study. This figure illustrates that nearly half of insulin secretion is lost at diagnosis. It also shows the progressive loss of insulin secretory reserve, which predicts essentially complete insulin deficiency in about a dozen years if further loss were linear.

FIGURE 2 Based upon a homeostasis (HOMA) model, residual maximal insulin secretory reserve is depicted at the time of diagnosis and yearly for 6 years in subjects receiving diet only in the U.K. Prospective Diabetes study. This figure illustrates that nearly half of insulin secretion is lost at diagnosis. It also shows the progressive loss of insulin secretory reserve, which predicts essentially complete insulin deficiency in about a dozen years if further loss were linear.

progressive disorder, mainly because of declining insulin secretion over time. It is hoped that current or future therapies, such as thiazolidinediones or glucagon-like peptide-1 (GLP-1) mimetics, may ameliorate this progressive insulin secretory dysfunction. However, rigorous evidence that any therapy has this benefit in humans is still lacking, despite some promising preliminary results.

Progressive Attenuation of the Response to Monotherapy

Presumably linked to the gradual loss of insulin secretory function, there is a decline in the effectiveness of any monotherapy (5). Figure 3 shows a gradual upward climb of HbAic for patients using either conventional or intensive policy in the UKPDS. The deterioration of metabolic control was not prevented by any of the monotherapy regimens, including injected insulin—although the insulin regimen was not consistently advanced to intensive insulin therapy. The ADOPT study showed a modest benefit of rosiglitazone to slow disease progression in comparison to metformin and glyburide.

FIGURE 3 This figure, which is adapted from the U.K. Prospective Diabetes study comparing conventional policy to intensive policy with sulfonylureas or insulin, shows the progressive rise of HbA1c that presumably is related to the progressive insulin secretory defect present in untreated type 2 diabetes mellitus.

FIGURE 3 This figure, which is adapted from the U.K. Prospective Diabetes study comparing conventional policy to intensive policy with sulfonylureas or insulin, shows the progressive rise of HbA1c that presumably is related to the progressive insulin secretory defect present in untreated type 2 diabetes mellitus.

Thus, type 2 diabetes is a progressive disease caused by progressive beta-cell dysfunction. It is the development of beta-cell dysfunction which initiates the transition from the metabolic syndrome of insulin resistance to impaired glucose tolerance and, ultimately, to diabetes. It appears that this progressive beta-cell dysfunction necessitates progressive therapy, including the use of combinations of agents. This insight is another major contribution from the UKPDS. As shown in Figure 1, type 2 diabetes has two defects that are crucial to the genesis of the disorder. This review, to some degree, simplifies the defects conceptually. Abnormalities of insulin secretion are both quantitative and qualitative, and include abnormal pulsatility, ultradian rhythms and clearance, but the net effect of these abnormalities is the lack of a timely insulin response for adequate compensation of insulin resistance (6). Similarly, insulin resistance is a complex phenomenon, with evidence of tissue-specific abnormalities and complex interactive effects. Again, the net effect is diminished biologic signaling of insulin action at multiple tissues, relative to the availability of insulin at a given moment. The molecular mechanisms underlying these defects still are only partly understood.

A Long Prodrome of Insulin Resistance Relates to Cardiovascular Disease

As indicated in Figure 1, tissue resistance to insulin action takes place long before the development of type 2 diabetes. Indeed, insulin resistance that precedes the development of type 2 diabetes by many years, may contribute greatly to the very high rate of cardiovascular events which account for the deaths of most people with this disorder (7). Haffner et al. have referred to a "ticking clock" hypothesis (8), suggesting that a long prodrome of insulin resistance before diabetes develops, associated with multiple cardiovascular risk factors (mildly abnormal glycemic patterns, dyslipidemia, hypertension, procoagulant and inflammatory state, etc.), sets the stage for the markedly increased risk of cardiovascular disease known to prevail once diabetes has been diagnosed (9). Resistance to the action of insulin occurs both in the traditionally insulin-sensitive tissues of the skeletal muscle and adipose tissue, and in the liver (10). Excessive production of glucose by the liver, despite insulin levels that are not markedly different from those of persons without diabetes and of similar adiposity, is one of the main causes of hyperglycemia in type 2 diabetes. Metformin's main action is to improve the hepatic response to insulin at least partly through its effects upon hepatic adenosine monophosphate kinase, which acts as a fuel sensor and thus controls the excessive hepatic glucose output. Resistance to insulin action at skeletal muscle and adipose tissue also affects glycemic control. An important effect of healthy eating and an active lifestyle is improved sensitivity of these tissues to insulin. Drugs of the thiazolidinedione class reduce peripheral resistance to the actions of insulin.

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Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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