The Importance of B-Cell Failure in the Development and Progression of Type 2 Diabetes
Journal of Clinical Endocrinology and Metabolism
Vol 86 No 9 4047-4058, 2001

Potential Mechanism for the progressive B-cell failure in the pathogenesis and progression of type 2 diabetes

1. Hypotheses for development of B-cell dysfunction in type 2 diabetes
• Mechanism One: B-cell exhaustion due to the increased secretory demand from insulin resistance
• Mechanism Two: Densentization of the B-cell due to the elevations in glucose
• Mechanism Three: Lipotoxicity
• Mechanism Four: Reduction of B-cell mass, possibly due to amyloid deposition

Conclusion

1. It is clear that B-cell dysfunction exists in individuals with type 2 diabetes.
2. This dysfunction is global involving a number of different measures of the functional integrity of the B-cell.
3. The degree of B-cell dysfunction is related to degree of hyperglycemia.
4. B-cell dysfunction is present before the fasting and/or 2-h glucose levels reach the diagnostic cut points for diabetes.

B-cell dysfunction is present before the development of type 2 diabetes

1. Insulin sensitivity and B-cell function are inversely and proportionally related so that the product of these two parameter is always a constant.
2. This constant is called the disposition index.
3. Any change in insulin sensitivity is balanced by a reciprocal and proportionate change in B-cell function

Outline of Article

Type 2 Diabetes pathogenesis is complex and requires defects in both:

• B-Cell function
• Insulin Sensitivity

Together, these two result in:

• increased rates of glucose release by the liver and kidney
• decreased clearance of glucose from the circulation

Progressive nature of type 2 diabetes has been clinically recognized:

• Very difficult to maintain individuals at target HgbA1C
• United Kingdom Prospective Diabetes Study (UKPDS) after 9 years only 25% of patient achieved a HbA1c less than 7% with intensive therapy on monotherapy.

The reason for the progressive deterioration in glycemic control in the UKPDS was addressed by the Homeostasis Model Assessment (HOMA).

• The reason for the progressive nature of DM type 2 is an ongoing decline in b-Cell function without a change in insulin resistance.
• Belfast diet intervention study showed the same thing.

The nature of B-Cell dysfunction in type 2 diabetes

1. For hyperglycemia to exist in type 2 diabetes, B-cell dysfunction has to be present.


2. B-cell function is altered in a number of different ways:


• Reductions in insulin release in response to glucose
• Reduction in insulin release in response to nonglucose secretagogues
• Changes in pulsatile and oscillatory insulin secretion
• Abnormality in the efficiency of proinsulin to insulin conversion
• Reduced release of islet amyloid polpeptide (IAPP), also known as amylin.


1. Reductions in insulin release can be demonstrated in type 2 diabetes following oral glucose loading


• The absolute response occurring early (30 mins) are reduced
• The latter response may be greater because more glucose in delivered due to early insulin decrease.
• Early phase insulin response and glucose tolerance s nonlinear.
• Small decreases in early response can have dramatic effects on later glucose excursion.
• Large changes may have a small effect in individuals with normal glucose tolerance.


2. Dynamics of insulin release has two phases:


• First-phase response peaks within 2-5 mins, last approximately 10 min, and is thought to represent the release of a pool of secretory granules present in close proximity to the B-Cell plasma membrane.
• Second-phase response is maintained for as long as the glucose level is elevated, and is believed to represent the release of granules that are being mobilized within the B-cell.


3. In type-2 diabetes both these responses are diminished.


• The lack of a first-phase is a sine quo non for diabetes
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• he first-phase is absent in all individuals with hyperglycemia.


4. 50-75% of the secretory capacity of the B-cell is lost by the time fasting hyperglycemia develops.


5. Because fasting hyperglycemia is a relatively late event in the pathogenesis of diabetes and B-cell dysfunction is progressive, lesser reductions in B-cell secretory capacity will be associated with reduced glucose tolerance before fasting hyperglycemia is manifest.


6. The UKPDS supported this with a finding that 50% of the B-cell function was lost at the time of diagnosis of fasting hyperglycemia.

Insulin release can occur in both a pulsatile and an oscillatory manner.

1. These pulses originate in the islet.
2. Isolated islets in culture demonstrate the presence of these pulses despite the fact that they lack heir neural connection.
3. In type 2 diabetes, the pulsatile pattern of insulin release is disrupted.
4. The loss of these pulses also play a role in insulin resistance as delivery of insulin as a continuous infusion is associated with impaired insulin action.
5. The rapid pulses are superimposed on larger oscillations in insulin release.
6. Oscillations have a phase of approximately 120 minutes.
7. It is uncertain what regulates these longer oscillations but may arise from signaling outside the islet.
8. The natural oscillations are defective in type 2 diabetes.

Disturbed insulin biosynthetic process

1. Insulin production requires the cleavage of insulin out of its larger precursor peptide proinsulin resulting in the formation of insulin and C-peptide.
2. This occurs within the secretory granule while it transits the B-cell and matures.
3. In type 2 diabetes, the efficiency by which the cell processes proinsulin is reduced.
4. The degree of proinsulin (2 to 3 times the normal) is linearly related to the degree of hyperglycema.

Cosecretion of islet amyloid polpeptide (IAPP), also known as amylin

1. IAPP is located with insulin in the B-cell secretory granule.
2. It is secreted along with insulin in response to glucose and other stimuli.
3. IAPP is diminished in individuals with type 2 diabetes.
4. IAPP has been shown to slow gastric emptying and thus delay glucose absorption.
5. Whether IAPP can induce insulin resistance is unclear.

Conclusion

5. It is clear that B-cell dysfunction exists in individuals with type 2 diabetes.
6. This dysfunction is global involving a number of different measures of the functional integrity of the B-cell.
7. The degree of B-cell dysfunction is related to degree of hyperglycemia.
8. B-cell dysfunction is present before the fasting and/or 2-h glucose levels reach the diagnostic cutpoints for diabetes.

B-cell dysfunction is present before the development of type 2 diabetes

4. Insulin sensitivity and B-cell function are inversely and proportionally related so that the product of these two parameter is always a constant.
5. This constant is called the disposition index.
6. Any change in insulin sensitivity is balanced by a reciprocal and proportionate change in B-cell function

All of the following can be shown to have a reduced First-phase response to glucose

1. First-degree relatives of individuals with type 2 diabetes
2. Women with history of gestational diabetes
3. Women with polycystic ovarian disease
4. Older subjects
5. Individuals with impaired glucose tolerance

The vast majority of individuals who have two first-degree relatives with type 2 diabetes fall below the mean (50th percentile) for the relationship between insulin sensitivity and insulin secretion, in keeping with their high-risk status.

Potential Mechanism for the progressive B-cell failure in the pathogenesis and progression of type 2 diabetes

2. Hypotheses for development of B-cell dysfunction in type 2 diabetes


Mechanism One: B-cell exhaustion due to the increased secretory demand from insulin resistance
Mechanism Two: Densentization of the B-cell due to the elevations in glucose
Mechanism Three: Lipotoxicity
Mechanism Four: Reduction of B-cell mass, possibly due to amyloid deposition

3. Mechanism One: Insulin resistance increases the secretory function of the B-cell.


• The idea that this leads to B-cell exhaustion may not be a fact. The following argue against that.
• First, insulin resistance is common, occurring in almost all obese subjects. Even so, only a small proportion of obese individuals ultimately develop diabetes.
• Second, the Pima Indian study highlights the fact that B-cell function is enhanced in apparently health subjects as insulin resistance progresses.
• Third, induction of short-term experimental insulin resistance with nicotinic acid is associated with adaptive increase in B-cell function manifested as increased insulin release and a decrease in proportion of proinsulin in plasma.
• Therefore, it would seem that a failure to adequately adapt to insulin resistance may be due to a genetically programmed B-cell abnormality associated with an inability of the normal B-cell to adapt to insulin resistance and increased secretory demand thus uncovering a defect in B-cell function.
• On the other hand, the B-cells in those without such a genetic issue would adapt and prevent the development of hyperglycemia.

4. Mechanism Two: Glucose has been suggested to not only be a B-cell stimulant but to also potentially modify B-cell function in a deleterious manner.


• This is known as “glucose toxicity” or “glucose desensitization.”
• There is research evidence that glucose decreased B-cell response to secretagogues.
• Balancing these findings are observations in humans that would suggest that glucose toxicity may not be a primary factor in the loss of B-cell function.
• The UKPDS findings suggest that in the early stages of diabetes, glucose is unlikely to be a critical factor in determining the progression of B-cell dysfunction.
• The glucose toxicity effect is likely to occur later rather than earlier and may well contribute to B-cell dysfunction once this secretory abnormality is present.

5. Mechanism Three: Diabetes is a global metabolic disorder that is also characterized by changes in fat and protein metabolism


• Data in animal models suggest that lipid changes may contribute to the development of B-cell dysfunction.
• Westernization and the accompanying increase in dietary fat intake may contribute to alterations in B-cell function.
• Increase in dietary carbohydrate and decrease in dietary fat resulted in improved glucose tolerance as a result of an increase in insulin secretion and an improvement in insulin sensitivity in older subjects and individuals with type 2 diabetes.
• As the development of obesity commonly results in increased intra-abdominal fat that appears to be metabolically active fat depot it is possible that factors emanating from fat may bee the critical mediator.

1. Free fatty acids is one candidate.
2. Fluctuations of FFA are known to be critical to B-cell function.
3. Chronic increases of FFA may be deleterious to B-cell function


• This seems to result not only in a decline in insulin release but also may have an effect to reduce the efficiency of proinsulin to insulin conversion within the B-cell.
• Other candidate molecules form fat may play a role in B-cell function decrease:


1. Leptin
2. Cytokine TNF-alpha

4. Mechanism Four: Reduced B-cell mass potentially explains impaired maximal secretory capacity for insulin secretion


• The reduction in mass cannot explain the entire pattern of fucnitoal changes observed intype 2 diabetes.
• The etiology of the mass reduction may be multifactorial.
• Apotysis programmed cell death may increase as a result of the deranged metabolicstae such as elevation in glucose and free fatty acids.
• Amyloid deposits provides another plausible mechanism o explain a portion of the reduced B-cell mass.

The exact mechanism for pathogenesis of impairments to B-cell function in type 2 diabetes is not known. A model for the interaction of dietary fat, glucose and islet amyloid is possible.

1. An individual who is genetically determined to be at risk of developing type 2 diabetes
2. A prolonged increase of dietary fat intake
3. Induces B-cell dysfunction

This reduction in function results in reduced insulin secretion that in turn results in hyperglycemia.

1. This also results in changes to how the B-cell handles IAPP and allows islet amyloidgenesis to occur.
2. As these deposits increase, they replace B-cell mass further aggravating the ability of the islet to produce and secrete insulin
3. Sustain hyperglycemia in the face of impaired B-cell function further aggravates B-cell function as a result of “glucose toxicity.”
4. These effects feed forward aggravating the clinical syndrome and in most individuals requiring increases in therapy aimed at reducing hyperglycemia.

The future for preventing the progressive B-cell failure of type 3 diabetes

1. A number of possible mechanism for B-cell dysfunction of type 2 diabetes.
2. Hyperglycemia and free fatty acids contributing would imply that aggressive control of both would result in improved insulin release and prevention of progression.
3. UKPDS showed a continuation of the decline of B-cell function even with excellent control of glucose and free fatty acids.
4. The effect of control of lipids is yet to be determined.
5. As the deposition of islet amyloid would be predicted to result in an ongoing loss of B-cell mass, it is possible that a small nidus of amyloid could be sufficient to explain the early progressive failure of B-cell function observed in type 2 diabetes.
6. Inhibition of the amyloidogenic process may well require the development of inhibitors that prevent the binding of secreted IPAA to formed fibils, well before large amounts of amyloid are visible by light microscopy.
7. Recent observation related to peroxisome proliferators-activated receptor-gamma raise possibilities.
8. Resistin, a peptide that is produced and secreted by adipocytes and is capable of inducing insulin resistance opens avenues for research.
9. Reports of a potential effect of thiazolidinediones to preserve B-cell function in animal models of diabetes provides impetus for clinical testing.

Conclusions

1. Hyperglycemia has conclusively been demonstrated to be an important contributing factor in the development of the ravaging complications of type 2 diabetes.
2. The challenge to attain and maintain normoglycemia is compounded by the progressive nature of the disease.
3. The progression seems to be due to a continuous decline in B-cell function that starts many years before diagnosis.
4. Even though a greater number of therapeutic options are available for lowering plasma glucose, none have been shown to reliably slow the progressive loss of B-cell function.
5. Future filled with challenges that will involve genetic, physiological and pharmacological approaches that likely will have to focus early on the B-cell to be beneficial.