Elsevier

Archives of Medical Research

Volume 36, Issue 3, May–June 2005, Pages 197-209
Archives of Medical Research

Review article
Pathogenesis of Type 2 Diabetes Mellitus

https://doi.org/10.1016/j.arcmed.2005.01.003Get rights and content

The pathological sequence for type 2 diabetes is complex and entails many different elements that act in concert to cause that disease. This review proposes a sequence of events and how they interact by a careful analysis of the human and animal model literature. A genetic predisposition must exist, although to date very little is known about specific genetic defects in this disease. Whether the diabetes phenotype will occur depends on many environmental factors that share an ability to stress the glucose homeostasis system, with the current explosion of obesity and sedentary lifestyle being a major cause of the worldwide diabetes epidemic. We also propose that a lowered beta-cell mass either through genetic and/or beta-cell cytotoxic factors predisposes for glucose intolerance. As the blood glucose level rises even a small amount above normal, then acquired defects in the glucose homeostasis system occur—initially to impair the beta cell's glucose responsiveness to meals by impairing the first phase insulin response—and cause the blood glucose level to rise into the range of impaired glucose tolerance (IGT). This rise in blood glucose, now perhaps in concert with the excess fatty acids that are a typical feature of obesity and insulin resistance, cause additional deterioration in beta-cell function along with further insulin resistance, and the blood glucose levels rise to full-blown diabetes. This sequence also provides insight into how to better prevent or treat type 2 diabetes, by studying the molecular basis for the early defects, and developing targeted therapies against them.

Introduction

Type 2 diabetes is a worldwide health crisis. The figures in the U.S. are disturbing—18.1 million affected at a cost of $132 billion in 2002 (1)—and likely to get much worse. The Centers for Disease Control and Prevention estimates there are 40 million people in the U.S. with prediabetes, and the Diabetes Prevention Program (U.S. study that investigated the effect of lifestyle intervention or metformin to prevent progression of impaired glucose tolerance (IGT) to diabetes) showed an 11% conversion per year of IGT going to diabetes (2), which means 2 to 4 million new diabetes cases each year. Furthermore, the incidence of type 2 diabetes is increasing worldwide, often in countries that cannot meet the resulting medical and financial burdens (3), with a recent study predicting the worldwide prevalence of diabetes will increase from 2.8% in 2000 to 4.4% in 2030, resulting in 366 million affected people (4).

Much of the current crisis stems from our modern lifestyle with the abundance of high calorie foods along with lowered energy expenditure because of the wide availability of cars, TV watching, fewer outside activities, etc. Also, the worldwide trend of developing societies shifting away from an agrarian existence to city living and less physically demanding office and factory jobs also is taking its toll. In the U.S., these changes have been most evident for children and countless papers have reported on the epidemic of childhood obesity (5) and its root causes of TV watching, eating fast food, etc. 6, 7.

One can predict that returning to healthy lifestyles would reverse the rising incidence of type 2 diabetes. Unfortunately, that is not a practical solution. Instead, the current approach is to better understand the pathogenesis of type 2 diabetes, hopefully followed by the development of pharmaceuticals that reverse the key pathogenic elements. We entered the 1990s knowing that type 2 diabetes was characterized by the classic triad of β-cell dysfunction, excess glucose production from the liver, and insulin resistance defined as impaired insulin-mediated glucose clearance into skeletal muscle (8). However, knowledge at that time provided no physiological connection between these organs. Another conundrum was how excess adiposity, i.e., being fat, caused insulin resistance, which again is a defect in skeletal muscle physiology.

Considerable progress has occurred over the last decade in our understanding of type 2 diabetes although all of the answers are not in yet. This review will provide an overview of the current understanding of how this disease develops, with Figure 1 showing the main pathogenic factors to be discussed.

Section snippets

Genetic Predisposition

The fact that type 2 diabetes is a genetic disease is well known to clinicians by how it occurs in families, and by there being ethnic populations who are particularly high risk. The genetic link was clearly shown more than two decades ago by a famous study of identical twins in the U.K. that found essentially a 100% concordance rate for this disease—if one twin developed type 2 diabetes, then the other one invariably developed it (9). However, this kind of study provides no insight into how

Environment

The second factor in Figure 1 is environmental aspects. An important concept is the diabetes genotype typically causes only a predisposition for glucose intolerance (note the terminology susceptibility gene was used in the preceding paragraphs). Whether one develops the diabetes phenotype depends on environmental factors, some obvious in how they act, others less so. For instance, the Nurses Health Survey showed positive associations between obesity and lack of physical activity in the

Acquired Organ Dysfunction

The third element on the top of Figure 1 is acquired defects. This refers to additional defects in glucose homeostasis that occur as the diabetes metabolic environment develops. This concept was first identified by studies that intensively treated persons with type 2 diabetes to bring blood glucose values as close to normal as possible, and noted improved beta-cell function (20), with later studies also showing some reversal of insulin resistance. This reversal effect is unrelated to the type

Insulin Resistance vs. Beta-Cell Dysfunction

Figure 1 (bottom) shows one of the most controversial topics within the field of type 2 diabetes over many years—is this a disease of insulin resistance or beta-cell dysfunction? The confusion for many years was both defects were invariably present when persons with type 2 diabetes were investigated and also when persons with IGT were studied. Attempts to go earlier in the course of the disease by studying persons at high-risk who were still normoglycemic—high-risk ethnic groups such as Pima

Beta-Cell Dysfunction in Type 2 Diabetes

Studies over many years have described the types of beta-cell dysfunction that characterize this disease—Reference (48) is a comprehensive review of the subject. The major defects are that insulin is normally secreted in a pulsatile fashion, with oscillations every 11 to 14 min that are thought necessary for normal regulation of hepatic glucose production (49), and large bursts (termed ultradian oscillations) several times a day, especially after meals, to maximize the efficiency of nutrient

Lowered Beta-Cell Mass in Type 2 Diabetes

The prior discussion was of beta-cell functional abnormalities in type 2 diabetes. A more recent research focus concerns abnormalities in the mass of beta cells. The measurement of beta-cell mass in humans is extremely difficult and must be done on autopsy specimens. Until recently there were few studies of this topic, and all with only a few subjects. Further confusing the issue was a lack of appropriately matching subjects with type 2 diabetes to weight-matched controls in many of the

Cellular Mechanisms of Beta-Cell Dysfunction

There has been intense study of potential cellular mechanisms of the beta-cell dysfunction in type 2 diabetes, although for the most part these studies have been carried out in vitro after exposing isolated islets or beta-cell clonal cell lines to abnormally high glucose levels, or by studying isolated islets from diabetic animals. A major impediment in this field has been the inability to get islet tissue from free living humans. Several mechanisms have been proposed, but none definitively

Insulin Resistance in Type 2 Diabetes

Insulin resistance is defined as impaired insulin-mediated glucose clearance into target tissues. Physiology studies many years ago showed most of the insulin-mediated clearance of a glucose load goes into skeletal muscle, plus the insulin response to the meal shuts down hepatic glucose production. We now know that the defect with insulin resistance is at both sites. In the fasting state, the degree of hyperglycemia is directly determined by the rate of glucose overproduction by the liver. With

What Is the Link Between Adiposity and Insulin Resistance?

One of the great questions some years ago was how is insulin resistance caused by becoming fat? A breakthrough in this subject occurred with the discovery that adipose tissue is more complex than simply acting as a storage site for triglyceride. In particular, adipocytes have been shown to produce many proteins (adipokines) that have peripheral effects on many tissues including skeletal muscle and liver and concurrently insulin sensitivity (104).

Of particular interest for skeletal muscle are

Summary

The pathological sequence for type 2 diabetes shown in Figure 1 entails many elements. It is believed to be mandatory to have a genetic predisposition that is currently poorly understood. Whether the diabetes phenotype then occurs is influenced by many environmental factors that share an ability to stress the glucose homeostasis system, either by causing or worsening insulin resistance or impairing insulin secretion. We also propose that a lowered beta-cell mass through genetic or beta-cell

Acknowledgement

The author receives research funds from the American Diabetes Association and the National Institutes of Health (DK-56818, DK-66635, DK-68329).

References (113)

  • L.Y. Qiao et al.

    Identification of enhanced serine kinase activity in insulin resistance

    J Biol Chem

    (1999)
  • V. Aguirre et al.

    Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action

    J Biol Chem

    (2002)
  • S. Marshall et al.

    Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance

    J Biol Chem

    (1991)
  • D. Spampinato et al.

    Rats that are made insulin resistant by glucosamine treatment have impaired skeletal muscle insulin receptor phosphorylation

    Metabolism

    (2003)
  • G. Boden et al.

    Nutritional effects of fat on carbohydrate metabolism

    Best Pract Res Clin Endocrinol Metab

    (2003)
  • P. Hogan et al.

    American Diabetes Association. Economic costs of diabetes in the US in 2002

    Diabetes Care

    (2003)
  • W.C. Knowler et al.

    Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin

    N Engl J Med

    (2002)
  • P. Zimmet et al.

    The global NIDDM epidemic. Treating the disease and ignoring the symptom

    Diabetologia

    (1996)
  • S. Wild et al.

    Global prevalence of diabetes: estimates for the year 2000 and projections for 2030

    Diabetes Care

    (2004)
  • A.A. Hedley et al.

    Prevalence of overweight and obesity among US children, adolescents and adults, 1999–2002

    JAMA

    (2004)
  • M.B. Schulze et al.

    Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women

    JAMA

    (2004)
  • M. Caroli et al.

    Role of television in childhood obesity prevention

    Int J Obes Relat Metab Disord

    (2004)
  • A.H. Barnett et al.

    Diabetes in identical twins. A study of 200 pairs

    Diabetologia

    (1981)
  • C.L. Hanis et al.

    A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2

    Nat Genet

    (1996)
  • Y. Horikawa et al.

    Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus

    Nat Genet

    (2000)
  • C. Marshall et al.

    Evidence that an isoform of calpain-10 is a regulator of exocytosis in pancreatic β-cells

    Mol Endocrinol

    (2005)
  • J.C. Florez et al.

    Association testing in 9,000 people fails to confirm the association of the insulin receptor substrate-1 G972R polymorphism with type 2 diabetes

    Diabetes

    (2004)
  • F.B. Hu et al.

    Diet, lifestyle, and the risk of type 2 diabetes mellitus in women

    N Engl J Med

    (2001)
  • K. O'Dea

    Marked improvement in carbohydrate and lipid metabolism in diabetic Australian aborigines after temporary reversion to traditional lifestyle

    Diabetes

    (1984)
  • R. Weiss et al.

    Obesity and the metabolic syndrome in children and adolescents

    N Engl J Med

    (2004)
  • X.R. Pan et al.

    Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study

    Diabetes Care

    (1997)
  • J. Tuomilehto et al.

    Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance

    N Engl J Med

    (2001)
  • S.W. Rizkalla et al.

    Improved plasma glucose control, whole-body glucose utilization, and lipid profile on a low-glycemic index diet in type 2 diabetes

    Diabetes Care

    (2004)
  • R.C. Turner et al.

    Beta-cell function improved by supplementing basal insulin secretion in mild diabetes

    Br Med J

    (1976)
  • K. Kosaka et al.

    Increase in insulin response after treatment of overt maturity-onset diabetes is independent of the mode of treatment

    Diabetologia

    (1980)
  • Y. Li et al.

    Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of beta-cell function

    Diabetes Care

    (2004)
  • A.L. Peters et al.

    Maximal dose glyburide therapy in markedly symptomatic patients with type 2 diabetes: a new use for an old friend

    J Clin Endocrinol Metab

    (1996)
  • W.T. Garvey et al.

    The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus

    Diabetes

    (1985)
  • L. Rossetti et al.

    Glucose toxicity

    Diabetes Care

    (1990)
  • J.L. Leahy et al.

    Beta-cell dysfunction induced by chronic hyperglycemia: current ideas on the mechanism of the impaired glucose-induced insulin secretion

    Diabetes Care

    (1992)
  • J.L. Leahy et al.

    Chronic hyperglycemia is associated with impaired glucose influence on insulin secretion. A study in normal rats using chronic in vivo glucose infusions

    J Clin Invest

    (1986)
  • L. Rossetti et al.

    Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats

    J Clin Invest

    (1987)
  • J.D. McGarry et al.

    Fatty acids, lipotoxicity and insulin secretion

    Diabetologia

    (1999)
  • M. Prentki et al.

    Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes

    Diabetes

    (2002)
  • V. Poitout et al.

    Minireview: Secondary beta-cell failure in type 2 diabetes–a convergence of glucotoxicity and lipotoxicity

    Endocrinology

    (2002)
  • J.E. Gerich

    The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity

    Endocr Rev

    (1998)
  • M.J. Perley et al.

    Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects

    J Clin Invest

    (1967)
  • S. Lillioja et al.

    Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians

    N Engl J Med

    (1988)
  • S. Lillioja et al.

    Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians

    N Engl J Med

    (1993)
  • M.K. Cavaghan et al.

    Interactions between insulin resistance and insulin secretion in the development of glucose intolerance

    J Clin Invest

    (2000)
  • Cited by (388)

    • Recent advancements on novel approaches of insulin delivery

      2023, Medicine in Novel Technology and Devices
    View all citing articles on Scopus
    View full text