Diabetes and Lipid Clinic of Alaska

 

 


Insulin Resistance and the Development of Diabetes

Type 2 Diabetes and Insulin Resistance

Type 2 Diabetes Mellitus is a metabolic disease characterized by hyperglycemia due to defective insulin secretion, insulin action or both. It is the defective insulin action or Insulin Resistance that is one of the greatest challenges in diabetes management. Traditionally, our thinking has been that it is the chronic glucose elevation of diabetes that leads to the damage and dysfunction to the kidney, eye, nerves and blood vessels. We are now realizing that the risks and damage may start years before blood glucose levels rise above normal.

There is currently an epidemic of Type 2 diabetes throughout the world that is rapidly worsening. The cost in lives lost and the financial cost of dealing with the medical complications of diabetes is staggering. It is only by understanding and developing effective treatment for Insulin Resistance that we can hope to deal to this threat to our lives and health.

Pathogenesis of Type 2 Diabetes

Insulin resistance is the earliest detectable abnormality in pre-diabetic individuals. Insulin resistance may start years or even decades before the diagnosis of diabetes is made on the basis of a fasting plasma glucose greater than 126 mg/dl.. The difficulty is that we really don’t have any easy way of identifying and measuring insulin resistance. We have tried various models of measuring insulin resistance but they have not been useful in clinical practice.

Insulin resistance is defined as an impaired response to either insulin, either injected or insulin coming from the pancreas (12).

Insulin resistance by itself does not cause diabetes. As long as the pancreatic beta cell, the pancreas cell which makes insulin, can compensate for the insulin resistance by producing more insulin; glucose levels will remain normal. It is only when the beta cell becomes impaired and insulin secretion is inadequate to compensate for insulin resistance that glucose levels rise. Initially there may be adequate insulin production in the fasting state but an inability for the pancreas to cope with the stress of high carbohydrate intake resulting in high glucoses after eating. This stage may be diagnosed by elevated 2 hr glucose on the standard glucose tolerance test. Normal is less than 140 after 2 hours. This stage is known as impaired glucose tolerance and is a precursor of Type 2 Diabetes.

Initially insulin resistance is compensated by over production of insulin by the pancreas. As the beta cell becomes exhausted and can no longer keep up, we develop impaired glucose tolerance (IGT). As the insulin defect progresses, glucose levels rise still further and when the fasting plasma glucose level exceeds 200, diabetes can diagnosed. The diagnosis of diabetes is based on a glucose level but the defect that caused this glucose level has been present for years. The first manifestation of disease has been insulin resistance and elevated serum insulin levels. In 1988 Gerald Reaven recognized a cluster of risk factors commonly present in individuals with high insulin levels (Reaven G. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-1607). This was initially referred to as syndrome X and is characterized by high blood pressure, abdominal obesity, high triglycerides, low HDL and impaired glucose tolerance. Insulin resistance is the common denominator of the syndrome. In 1998 the World Health Organization called this The Metabolic Syndrome.

Individuals with the metabolic (insulin resistance) syndrome are at dramatically elevated risk for diabetes, heart disease, stroke, kidney failure, blindness and nerve disease. People with diabetes have up to four times the risk of developing heart disease of age matched non diabetics.

What causes insulin resistance?

Insulin resistance can be triggered by obesity, pregnancy, aging or infections. Obesity and particularly abdominal obesity is associated with decreased levels of insulin mediated glucose uptake but is the obesity the cause or the effect of insulin resistance (3). Abdominal fat tissue could provide a chain of events leading to skeletal muscle insulin resistance which appears to be the first step in the cascade leading ultimately to Type 2 Diabetes. 90% of glucose is normally taken up into the muscles. There are certainly genetic factors in the development of Type 2 Diabetes and the first of these may be the genetic factor for abdominal obesity (4).

Another factor is possibly the “Thrifty Gene”. This is a genetic adaptation which would enhance survival in individuals living in an environment of frequent famine. (5). In times of plenty, this genetic background could become detrimental.

Low birth weight is also a risk factor for development of insulin resistance and diabetes mellitus (6).

It is unlikely that a single genetic variant is the cause of insulin resistance and type 2 diabetes. It is more likely that there are multiple genetic and environmental factors.

We can test for some of these abnormal genes at Diabetes and Lipid Clinic of Alaska.

Treatment of Insulin Resistance in Type 2 Diabetes

Insulin resistance is the first abnormality seen in the individual who will develop type 2 diabetes. Initially, there is elevated insulin levels but as the pancreas can no longer able to produce the increased amounts of insulin needed for glucose control. That is, relative insulin deficiency results and glucose levels start to rise. When a critical plasma glucose level is reached, we diagnose diabetes. Elevated insulin levels and the cluster of related symptoms such as high triglycerides, low HDL, obesity, high blood pressure, protein in the urine leads to increased risk of death and illness. Logically, we should direct our treatment to the reduction of insulin resistance.

Lifestyle Measures

Exercise: Exercise is one of the most effective means at our disposal to improve insulin resistance. Exercise is therefore one of the cornerstones of treatment of type 2 diabetes.

Diet: Even a modest weight loss of 5% of total body weight can lead to a significant improvement in insulin resistance and glucose control as well as improving cholesterol profile and lowering blood pressure.

Pharmacologic treatment: The object of pharmacologic treatment should be to improve insulin resistance as well as to reduce glucose levels

Please read information on this website about pre-diabetes, Type 2 diabetes in Children and Adults, Dietary considerations, review of medications, and genetic testing for diabetes. There is also a video for your review.


References

  1. Reaven G. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-1607
  2. Weyer C, Bogardus C, Mott D, Pratley R. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes. J Clin Invest 1999; 104: 787-794
  3. Groop L, Forsbloom C, Lehtovirta M et al. Metabolic consequences of a family history of NIDDM (the Botnia Study): evidence for sex specific parental effects. Diabetes 1996; 45: 1585-1593
  4. Bouchard C. Genetics of body fat content. In: Angel H, Anderson H, Bouchard C, Lau D, Leiter L, Mendelson R, eds. Progress in Obesity Research 7. John Libbey: London 1996; 7: 33-41
  5. Neel V. Diabetes mellitus: a ‘thrifty’ genotype rendered detrimental by progress? Am J Hum Genet 1962; 14; 352-362
  6. Jacob S, Machann J, Rett K. Association of increased intramyocellular lipid content with insulin resistance in lean non diabetic offspring of type 2 diabetes subjects. Diabetes 1999; 48; 1113-1119
  7. Haffner SM, Lehto S, Ronnemaa T et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in non diabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339: 229-234
  8. Laasko M, Sarlund H, Mykkanen L. Insulin resistance is associated with lipid and lipoprotein abnormalities in subjects with varying degrees of glucose intolerance. Arteriosclerosis 1990; 10: 223-231
  9. UK Prospective Diabetes Study Group XI: Biochemical risk factors in type 2 diabetic subjects at diagnosis compared with age-matched normal subjects. Diabet Med 1994; 11: 534-544
  10. Haffner SM, Clinical relevance of the oxidative stress concept. Metabolism 2000; 49(suppl 1); 30-34
  11. Sowers JR, Lester MA. Diabetes & cardiovascular disease. Diabetes Care 1999; 22(suppl 3); C14-C20
  12. Sagel J, Collwell JA, Crook L et al. Increased platelet aggregation in early diabetes mellitus. Ann Intern Med 1975; 82: 733-738
  13. American Diabetes Association. Consensus development conference on insulin resistance. Diabetes 1998; 21: 310-314

The information on this Web page is provided for educational purposes. You understand and agree that this information is not intended to be, and should not be used as, a substitute for medical treatment by a health care professional. You agree that Diabetes and Lipid Clinic of Alaska is not making a diagnosis of your condition or a recommendation about the course of treatment for your particular circumstances through the use of this Web page. You agree to be solely responsible for your use of information contained on this Web page.

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