Chapter 67

## Abstract

Abstract

1. β-Cell dysfunction is an integral component of the pathogenesis of the hyperglycemia of type 2 diabetes mellitus. This dysfunction is associated with decreased insulin secretion as well as a decline in the release of the newly identified β-cell secretory product islet amyloid polypeptide (IAPP or amylin). Production of these hormones by the islet β-cell requires the packaging of their respective propeptides (proinsulin and proIAPP) into secretory granules, where they undergo processing by the proprotein convertases (proconvertase 1/3 (PC1/3) and proconvertase 2 (PC2)) to yield their mature products insulin and IAPP and the inert C-peptide, the latter as a byproduct of proinsulin processing. Proinsulin processing is incomplete, and small amounts of proinsulin are released along with insulin and C-peptide when secretory granule exocytosis is stimulated by glucose and nonglucose secretagogues.

2. Glucose-induced exocytosis of the secretory granule requires entry of glucose into the cell via the facilitative glucose transporter Glut-2 followed by its phosphorylation by glucokinase. The subsequent metabolism of glucose results in the production of adenosine triphosphate(ATP), which raises the ATP/adenosine diphosphate (ADP) ratio within the cell and closes the specific ATP-sensitive potassium channel. In the case of the nonglucose secretagogues, these act via the membrane phosphodiesterases or by activation of adenylate cyclase through the guanine-nucleotide binding proteins (G-proteins). All of these mechanisms are dependent on the mobilization of calcium from the extracellular space or from intracellular stores.

3. Glucose directly stimulates insulin secretion in a complicated manner involving at least two phases. In addition to stimulating insulin release directly, glucose also potentiates the β-cell response to other secretagogues. The secretory responsiveness of the β-cell is also modulated by other factors including the sensitivity of the peripheral tissues to insulin. The nature of this modulation is compatible with a feedback loop such that β-cell function increases reciprocally as insulin sensitivity declines. Knowledge of the nature of this relationship is important in the interpretation of β-cell-function testing in vivo.

4. In type 2 diabetes, β-cell dysfunction is manifest as an absence of the early (first) phase of glucose-induced insulin and IAPP secretion and a reduction in the later (second) phase response. In addition, the ability of glucose to potentiate the β-cell's response to nonglucose secretagogues is diminished. Finally, oscillatory insulin release is also abnormal in subjects with type 2 diabetes. Many of these changes in β-cell function can be demonstrated in subjects at high risk of developing type 2 diabetes at a time when their glucose tolerance is essentially normal. These individuals include women with a history of gestational diabetes or with polycystic ovary syndrome, older subjects, first-degree relatives of individuals with type 2 diabetes, and subjects with impaired glucose tolerance (IGT).

5. The etiology of the β-cell dysfunction of type 2 diabetes is incompletely understood. Both genetic and environmental factors are important. Islet mass is reduced by the deposition of islet amyloid which predominantly replaces β-cells. These amyloid deposits are comprised primarily of IAPP. A single amino acid substitution in IAPP has been described in a few Japanese subjects, but this change does not explain the development of islet amyloid in the vast majority of individuals with type 2 diabetes. Thus, the mechanism(s) responsible for islet amyloid deposition do not appear to be related to an abnormality in the IAPP gene but rather to an alteration in IAPP processing and secretion by the β-cell. While β-cell mass is reduced by the deposition of islet amyloid, this is not the sole explanation for its dysfunction, as β-cell mass reduction cannot reproduce the secretory abnormalities observed in the human form of the disease.

6. Alterations in proinsulin release have also been documented in subjects with type 2 diabetes. Using insulin immunoassays, approximately 15 percent of circulating immunoreactive insulin is comprised of proinsulin in healthy subjects. In patients with type 2 diabetes, this proportion is approximately doubled. Milder alterations have also been demonstrated in subjects who are at high risk of developing type 2 diabetes by virtue of their having had gestational diabetes, or in subjects who subsequently progress to diabetes at a time when they were not hyperglycemic. The explanation for this disproportionate proinsulinemia is debated. It is believed to be either the result of a primary abnormality in β-cell processing or an increase in secretory demand on the β-cell, resulting in the premature release of secretory granules that have not had sufficient time to fully process the proinsulin within them. A few rare genetic alterations in the proinsulin molecule have been documented, but these are not commonly associated with diabetes.

7. Mitochondrial disease-associated syndromes: Muscle and neurologic disorders with maternal inheritance have been identified as mitochondrial gene abnormalities usually due to deletion, duplication, or mutation of specific mitochondrial genes. These are associated with diabetes mellitus and pancreatic β-cell dysfunction. Recent cases have been described with only sensineural hearing loss and diabetes. Clinically the patients present with type 2 diabetes, but progress rather rapidly to insulin dependence. Some cases have GAD and islet cell antibodies, causing confusion with late onset type 1 diabetes. Insulin resistance may occur, but is late in the clinical course. The pancreatic β-cell is assumed to fail because of its high oxidative energy requirement. Clinical heterogeneity is common, presumably because of mitochondrial heteroplasmy and/or modifying genes and environmental effects.

8. Sensorineural hearing loss and diabetes; maternally inherited diabetes and deafness (MIDD): This is the most common mitochondrial syndrome without major neurologic or muscle dysfunction, and is heterogeneous in molecular origin. The most common defect is an A3243G mutation in a tRNA. MIDD is also associated with an A8296G mutation, and occasionally with a T3721C mutation. Identical genetic lesions are clinically heterogeneous.

9. Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): The A3243 mutation is occasionally associated with a severe neurologic disorder (MELAS). Patients may die young due to severity of the neurologic disorder. If they survive, diabetes is common. Other genetic defects may also present with this phenotype.

10. Kearns-Sayre syndrome (KS): Ophthalmoplegia, pigmentary retinopathy, plus neurologic findings under age 20 are the primary symptoms. Patients usually have a major mitochondrial deletion. Diabetes is frequently present.

11. Maturity onset diabetes of the young (MODY): MODY is a Mendelian genetic syndrome with onset before age 25. Five causative mutations have been identified to date. More kindreds have been recognized, in whom molecular diagnosis is not yet established. To date all cases have impaired β-cell function as the primary defect. Some patients develop insulin resistance and late β-cell failure. Patients are usually lean. The disease occurs worldwide. Prevalence is estimated to be 2 to 5 percent of type 2 diabetes patients. It is characterized by mild to severe insulin deficiency, depending on the specific molecular defect.

12. MODY-1: A mutation of hepatic nuclear factor-4α (HNF-4α). The disease is highly penetrant. One-third of patients require insulin treatment. Interference with glucose metabolism is the postulated defect. Three mutations have been described to date. Most known cases occurred in one large family. Complications may occur.

13. MODY-2: A mutation in glucokinase that usually affects both hepatic and pancreatic isozymes. Hyperglycemia is mild. MODY-2 is usually treated successfully with diet or oral agents. Forty-two mutations have been described to date. Complications were infrequent. Impaired β-cell function is the predominant lesion. Insulin sensitivity is usually normal, but insensitivity may be present late.

14. MODY-3: Mutations affecting HNF-1α (hepatic nuclear factor-1α) are the most common causes of this syndrome to date. Fifty mutations have been described. It is clinically more severe than MODY-2 and progresses relatively rapidly from impaired insulin secretion to insulin deficiency requiring insulin replacement. Complications develop at rates comparable to late onset type 2 diabetes. Patients usually develop hyperglycemia after puberty. It is not associated with obesity, dyslipidemia, or hypertension. Patients may develop insulin resistance with clinical hyperglycemia.

15. Hepatocyte nuclear factor-1β (HNF-1β): Mutations in HNF-1β are rare causes of a MODY-like syndrome. Such mutations may be associated with renal dysfunction.

16. MODY-4: A mutation of insulin promoter factor-1 (IPF-1). Only one family has been identified. Onset of hyperglycemia has been variable (17 to 67 years). The course is mild, and patients respond to diet or oral-agent treatment. One homozygous null mutation resulted in pancreatic agenesis, which was replicated in a targeted deletion in the mouse.

17. Candidate genes for type 2 diabetes mellitus: A large number of candidate genes have been screened. None has been definitely shown as a significant cause of this syndrome. A review of those implicated in β-cell function includes glucokinase; GLUT-2; components of the KATP channel (SUR-1, Kir6.2); the glucagon receptor; IAPP (amylin); GIRK-1; GIRK-2; glucagon; the glucokinase regulatory protein; the glucagon-like protein-1 receptor (GLP-1R); the insulin gene transactivator islet-1 (ISL-1, 1PF-1); the caudal type homeodomain-3 gene (CDX-3); proprotein convertase-2 (PCSK-2); hexokinase-1 (HK-1); mitochondrial FAD-glycerophosphate dehydrogenase (GPD-2); β-cell pyruvate kinase (PKN); and the CCK-β receptor. Many have been associated in some populations, but not others. Some have been associated with impaired β-cell function and/or IGT, but not type 2 diabetes. Some associations are with variants in promoter regions, others with mutations, and still others with nonfunctional polymorphisms. Problems have been related to inadequate sample size, heterogenous populations, ascertainment bias, genetic heterogeneity, inadequate phenotypic characterization, and other methodologic problems. The probable polygenic nature of the syndrome, with factors involving insulin secretion and action, is also a likely contributor to this relative lack of success.

18. Genome-wide scanning: Five groups have published genome-wide scan data in part or in full using the affected sib-pair approach. Only one has reported a potentially significant association in a Mexican-American population identified in Starr County, Texas, as 2Q37 near 2DS125. No other population study has confirmed this finding and, in several studies, linkage was excluded. The locus named NIDDM-1 is under active investigation to identify a mutation. However, no known candidate genes are present in this region.

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