Robertson 16s-23s.qxd

A B S T R A C T
Background. The American Diabetes
Association has established
recommendations for
Update on diabetes
diagnosis and
in a metabolism thatapproaches that of people without diabetes.
management
The dentist also can provide risk-reductionstrategies for people prone to develop dia-betes, and refer patients with signs and CAROLYN ROBERTSON, A.P.R.N., M.S.N., C.D.E.,
B.C.-A.D.M.; ANDREW JAY DREXLER, M.D.;
ANTHONY T. VERNILLO, D.D.S., Ph.D.
Methods. The authors describe criteria
for establishing a diagnosis of diabetes and
for identifying people at high risk of devel-
While dental patients routinely complete oping the disease. A combination of
oral interview during their initial visit, type 1 and type 2 diabetes mellitus is pre- Results. Patients with diabetes maintain
reveal anything suspect. Yet, while talking about gen- eral well-being, a patient may mention the classic signs research includes early clinical trials of islet cell transplantation and therapeutic cloning Rigorous
metabolic fatigue. When this is noted, the patient
control of should be referred to a physician for
islet cells and, thus, may offer a potential diabetes can immediate evaluation. Given the large
be achieved number of undiagnosed cases of diabetes
Conclusions. Rigorous metabolic control
through a in the United States (approximately 6 to
of diabetes can be achieved through a com- 7 million), dentists are in a position to bination of therapeutic modalities and the combination of
therapeutic making such referrals. Patients with
modalities undiagnosed diabetes have a high risk of
ventive strategies and refer patients with and the developing life-threatening systemic
signs and symptoms suggestive of diabetes establishment complications because they have not yet
and received treatment. Unrecognized dia-
Clinical Implications. The dentist and
physician must work together as a team to maintenance
achieve rigorous metabolic control of dia- of target signs of uncontrolled glucose levels—
outcomes. poor healing and infection (for example,
candidiasis, gingivitis and periodontitis DIAGNOSIS OF DIABETES
with significant bone destruction)—and correctly corre-lating them to the classic signs and symptoms of uncon- trolled diabetes can lead to an early diagnosis and established criteria for testing undiagnosed people. They suggest that all people aged 45 This article provides an update on the diagnosis and years and older, especially those with a body mass index greater than or equal to 25 kilo- Copyright 2003 American Dental Association. All rights reserved.
grams/square meter, should have a fasting RISK FACTORS IN THE
greater than 126 milligrams/deciliter is diagnostic DEVELOPMENT OF DIABETES.
for diabetes. If the FPG is 110 to 126 mg/dL, thenan oral glucose tolerance test, or OGTT, should be dObesity (a weight higher than 120 percent of performed to determine the degree of glucose ideal body weight or a body mass index higher intolerance. If the FPG score is less than 110 dHigh-risk ethnic background (African-American, mg/dL, the test should be repeated at three-year Hispanic, American Indian, Asian, Pacific intervals. While an FPG of more than 126 mg/dL is the preferred diagnostic test owing to its ease of dHypertension dHigh-density lipoprotein level lower than administration and lower cost, a random plasma 35 milligrams per deciliter or a triglyceride level glucose level of greater than 200 mg/dL in the presence of the classic symptoms also is accept- dA first-degree relative with diabetesdHistory of gestational diabetes or delivery of a able. In each instance, positive findings must be confirmed by repeat testing on a subsequent day.
dImpaired glucose tolerance or impaired fasting Neither the glycosylated hemoglobin, or HbA glycemia (history of blood sugar level between nor the OGTT measurements are currently rec- dHistory of vascular disease or polycystic ovarian ommended for initial diagnostic use because of their lack of reproducibility. Testing should beconsidered at a younger age and carried out morefrequently in people who are at high risk (Box).
both microvascular and macrovascular complica- While the American Diabetes Association does tions with lowered HbA1c. This test provides a not specify the age at which to begin this measure of the patient’s average glycemia over screening, the American Association of Clinical the preceding two to three months and is an Endocrinologists, or AACE, suggests that it excellent tool for monitoring patient outcomes6 should be initiated at the age of 25 years.2 Because the available data have failed to iden- ESTABLISHING TARGET OUTCOMES
tify the optimum level of control for particular While the management of the patient with dia- patients, consensus regarding the target HbA1c is betes should be determined individually, based on lacking. The American Diabetes Association rec- the patient’s clinical status and willingness to ommends an HbA1c of 7 percent, while the AACE actively participate in self-care, there are recom- recommends that a value of 6.5 percent is a rea- mended goals. These goals are designed to sonable goal, but targets 6.0 percent as the achieve near-normal metabolic control, prevent or optimal endpoint.1,6 Since the HbA1c only repre- CORRELATION BETWEEN GLYCOSYLATED HEMOGLOBIN
LEVEL AND MEAN PLASMA GLUCOSE LEVELS.
GLYCOSYLATED
MEAN PLASMA
HEMOGLOBIN (%)
GLUCOSE ( mg/dL)*
Copyright 2003 American Dental Association. All rights reserved.
defects that occur simultaneously:insulin resistance and insulin defi- RECOMMENDATIONS REGARDING PLASMA
GLUCOSE, BLOOD PRESSURE AND LIPIDS FOR
NONPREGNANT ADULTS WITH DIABETES.
patient with type 2 diabetes and itusually antedates the onset of the RECOMMENDED LEVEL
Glycemic Control (Plasma Glucose)
Blood Pressure
hepatic glucose output. Insulindeficiency develops over time—ini- * mg/dL: Milligrams per deciliter.
† mm Hg: Millimeters of mercury.
tially as a loss of first-phaseinsulin release with a compen-satory increase in the second sents the mean glucose level, glycemic control is phase. This hyperinsulinemic response does not best judged by the combination of the HbA persist and the insulin secretory capacity of the (performed routinely every three months) and the beta cell begins to wane. Eventually, the patient concurrent results of the patient’s blood glucose becomes increasingly more insulinopenic. Since monitoring. Patients can be taught to perform this is a pathophysiological response, every indi- glucose tests at home using glucose meters that vidual with type 2 diabetes has the potential to require a single drop of blood (obtained from mul- require supplemental insulin. The eventual need tiple sites including fingertips, forearm, upper for insulin therapy should be considered a sign of arm, thigh, calf and the fleshy part of the hand).
the disease’s progression rather than a failure of These systems are small, simple to use and inex- the patient. Treatment regimens for patients with pensive. They are sufficiently accurate to provide type 2 diabetes should address both the insulin immediate feedback, allowing the patient and resistance and insulin deficiency, and must provider to make informed and timely changes to include both nonpharmacological and pharmaco- the regimen. Most people with diabetes have a high frequency of wide fluctuations in blood sugar The patient with type 1 diabetes has an abso- levels; therefore, it is important to counsel the lute insulin deficiency. As a consequence, these patient to avoid checking blood glucose at the patients must receive insulin replacement. Oral same time of the day. Instead, glucose monitoring hypoglycemic agents do not restore insulin secre- should be done at a variety of times—premeal, tion. Nonpharmacological interventions can facili- postmeal, before and after exercise and at bed- tate control, but they can never substitute for time—to best determine the impact that food, activity and even stress can have on the ambient In the patient with type 2 diabetes, initial serum glucose level. The overall goal of diabetes treatment begins with nonpharmacological inter- management is to achieve a level of metabolic ventions, specifically, a healthful meal plan, exer- control that approaches that of a person without cise and, when appropriate, weight loss. The meal plan should be designed to promote overall healththrough optimal nutrition, to facilitate improved DIABETES MANAGEMENT
blood glucose and lipid levels, and to provide suf- Achieving metabolic targets that approach levels ficient calories to achieve or maintain reasonable commonly found in people without diabetes weight. Interestingly, only a moderate amount of requires treatment programs that are designed to weight loss is needed to improve insulin resis- reproduce as closely as possible the pattern of glu- tance. Currently, there are three approaches to cose and endogenous insulin levels that would the diabetic diet: general recommendations that have existed if the patient did not have the dis- emphasize the U.S. Department of Agriculture’s ease. The patient with type 2 diabetes has two Food Guide Pyramid, calorie-reduced plans using Copyright 2003 American Dental Association. All rights reserved.
TYPES AND DOSAGES OF ORAL HYPOGLYCEMIC AGENTS.
DOSES PER DAY
Secretagogues*
Insulin Sensitizers‡
Agents That Delay
Carbohydrate Absorption§
Combination Agents
* Stimulates beta cells.
† mg: Milligram(s).
‡ Stimulates glucose uptake by muscle and adipose tissue and reduces the liver’s glucose output.
§ Delays the gut’s glucose absorption.
aids in weightreduction. It isimportant to encourage patients to enroll in struc- Metformin, pioglitazone and rosiglitazone are tured programs that emphasize lifestyle changes, used to improve insulin sensitivity. Metformin including education, reduced fat (< 30 percent of improves sensitivity of the liver and reduces hep- daily energy), regular physical activity and reg- atic glucose output, while pioglitazone and rosigli- ular contact between enrollees (this refers to tazone improve peripheral glucose uptake at the group classes, peer support groups and even muscles. Selection should consider the limitations Internet chat rooms). Several studies have demon- of these drugs. For example, a commonly used strated that structured programs can produce insulin sensitizer, metformin, has been associated long-term weight loss of 5 to 7 percent of starting with intractable lactic acidosis. If a patient has weight.8 When these measures fail to allow the mild kidney disease, or is at risk of developing patient to meet the target HbA1c levels, then oral congestive heart failure, severe infection can sig- hypoglycemic agents must be instituted (Table 3).
nificantly increase the risk of lactic acidosis. Com- The best time to initiate therapy with oral munication with the patient’s primary physician hypoglycemic agents and the optimal choice for is warranted to determine if the drug should be the starting medication still is being debated. Three classes of oral hypoglycemic agents are Pioglitazone and rosiglitazone are thiazolid- available. Each class reduces plasma glucose iones that activate the peroxisome proliferator- levels by one or more methods: increasing insulin activated receptors, or PPARs.12 Activation of the secretion, reducing insulin resistance or delaying PPARs regulates the transcription of insulin- glucose absorption by the gut. Since insulin sensitive genes involved in the control of glucose resistance is present before the onset of type 2 production, transport and utilization, and they diabetes, and because the failing beta cell occurs participate in the regulation of free fatty acid later in the disease, many have argued that the metabolism. Stimulation of PPAR-gamma and therapy should be initiated with an insulin sensi- -alpha receptors increases the expression of tizer and that the sensitizers should be started another molecule called ABCA1 that exports before the metabolic control decompensates.9,10 cholesterol from macrophages. Thus, exploiting Copyright 2003 American Dental Association. All rights reserved.
INSULIN PREPARATIONS.
TYPE OF INSULIN
DURATION OF
Human
Regular
Analogs
Lispro
Insulin Mixtures*
* Humulin is manufactured by Eli Lilly, Indianapolis, Ind.; Novolin, Novo Nordisk Pharmaceuticals, Princeton, N.J.; Humalog, Eli Lilly; Novolog, Novo Nordisk Pharmaceuticals.
this pathway may be a way to control lipid levels, destruction of the pancreatic insulin-producing beta cells and results in profound insulin defi- Proponents of using secretagogues as initial ciency. As a consequence, these patients must therapy suggest that increasing insulin secretion receive insulin replacement. Insulin also is indi- rapidly lowers blood glucose levels, thus reversing cated for patients with type 2 diabetes who have the glucose toxicity caused by severe hyper- persistent hyperglycemia either due to progres- glycemia. With lowered blood glucose levels, the sive loss of insulin secretion, or acute decompen- beta cell may be able to resume more normal sation due to stress, illness, infection or concur- function. Regardless of the drug class selected, rent medications. Current insulin therapy, when it is used as monotherapy, a 0.5 to 2 percent however, has not been able to mimic normal phys- reduction in HbA1c can be expected.13 When com- iology. Several problems exist. First, insulin must bination therapy is used, either with a secreta- be injected subcutaneously three or more times gogue and sensitizer or with two sensitizers, there per day to mimic the required concentration of is a further glucose reduction, with HbA1c reduc- insulin both in the preprandial and postprandial tions of 0.7 to 1.7 percent.14, 15 Many feel that these state. Second, subcutaneous insulin injections prefixed dose combinations facilitate patient com- deliver insulin initially to the systemic circulation pliance and have synergistic properties that allow and only secondarily into the portal circulation.
Hence, it is not possible to achieve the normal endogenous portal-to-systemic insulin ratios.
Copyright 2003 American Dental Association. All rights reserved.
Finally, much of the insulin is injected in a form mine the actual insulin requirement. A variety of that is not initially soluble, leading to fluctua- factors may influence the effectiveness of the tions in serum insulin levels, even after injection insulin therapy. These factors include the injec- of the same dosage.15,16 Table 4 shows types of tion site, the depth of penetration, the lag time insulin preparations and their onset, peak and between injection and the meal, the food con- sumed, activity and stress. To achieve near- Recent advances in insulin therapy have been normoglycemia, insulin dosages must be altered designed to overcome some of these limitations.
to compensate for the impact of these variables.
Insulin algorithms are designed to deliver a Therefore, it is necessary to prescribe more than near-continuous supply of insulin to match the an exact set of insulin instructions. Patients must body’s basal requirements and provide larger be given guidelines for adjusting the insulin dose quantities (bolus) of insulin to ensure adequate proactively, as well as guidelines for responding glucose uptake at meals. Insulin can be adminis- to blood glucose levels that are outside of the tered using a traditional insulin syringe, an target range. Patient self-monitoring of blood glu- insulin pen or a subcutaneous continuous insulin cose levels, accompanied by a program of educa- pump, or SCII.17,18 Optimal insulin replacement tion, can give the patient the knowledge and skill therapy consists of regimens that provide for the basal and the bolus needs of the individual. Inother words, the regimen must be designed using PREVENTION
insulins with different action profiles (Table 4).
Reducing the risk factors for developing diabetes With SCII, only one insulin type is required, may be an important approach in the prevention either short- or rapid-acting insulin, because the of this disease, particularly type 2 diabetes. The system provides insulin continuously. When the incidence of type 2 diabetes in children and ado- patient wishes to increase the delivery of insulin lescents is increasing and may be related to for a meal or a snack or to react to an undesired dietary obesity. Although there are insufficient glucose level, a button is pushed to activate a data to make general recommendations, a recent American Diabetes Association consensus state- ment provides guidance regarding the preven- insulin pump is to release insulin continuously tion, screening and treatment of type 2 diabetes and thus maintain glucose homeostasis by pre- in young people.21 Aside from nonmodifiable risk venting significant glycogenolysis from the factors such as age, family history and genetics, a glycogen stores in the liver.20 If there is disrup- person can change his or her lifestyle to include tion in this finely tuned glucose control, then regular exercise, maintaining a healthful low-fat rapid and severe hyperglycemia results, with dia- diet, and visiting a physician and dentist on a betic ketoacidosis, or DKA. The signs and symp- regular basis. However, in a recently published toms of DKA include nausea, disorientation, survey, people with diabetes were somewhat less abdominal cramps and fatigue; these often likely to visit their dentists for routine exami- resemble flulike signs and symptoms. The den- nations and were somewhat more likely to visit tist should recognize signs and symptoms of DKA for dental care only when treatment was needed and call the physician immediately if the glucose (for example, cleanings, restorations and oral meter readings show severe hyperglycemia. The surgery).22 Furthermore, in the same survey, physician may instruct the dentist to administer adults with diabetes rated their overall oral a bolus of rapidly acting insulin from the health somewhat lower than did people without patient’s backup supplies of insulin and insulin diabetes (control group), and they rated the need to visit a physician as a higher priority than did In type 1 diabetes, where insulin resistance is control subjects.22 Clearly, preventive strategies usually not a factor, patients will require approxi- must be in place for people, particularly those at mately 0.5 to 1.0 units of insulin/kilogram per 24 risk of developing diabetes, and for those with hours (most will require 0.6 U/kg).15,17 Patients diagnosed disease. The dentist can have a major with type 2 diabetes may require from 0.3 to 1.5 role, not only in the implementation of preven- U/kg. In both cases, body type (lean patients often tive strategies in both types of patient popula- require fewer insulin units/kilogram), activity, tions, but also in modifying oral health percep- stress and residual endogenous insulin will deter- tions and counterproductive attitudes.
Copyright 2003 American Dental Association. All rights reserved.
PANCREAS AND ISLET TRANSPLANTATION
advance toward the cure for diabetes mellitus, as THERAPY/STEM CELL RESEARCH
well as possibly other chronic debilitating dis-eases of our time.
Pancreas and islet transplantation are not rou-tine management options. In each case, the GENE THERAPEUTICS
patient requires immunosuppressive therapy, While cell transplantation and stem cell research which comes with associated risks. In general, are approaches that ultimately may provide pancreas transplantation, a major surgical inter- sources of insulin-producing cells, the promising vention, is considered only when a patient application of in vivo gene transfer may produce requires another transplantation—usually a therapeutic proteins or hormones.28 Salivary kidney. However, the success rate at one year for glands are recognized as classic exocrine glands, simultaneous kidney-pancreas transplantations is yet they also may secrete in an endocrine manner at 90 percent.23 While islet transplantation has (that is, directly into the bloodstream).29 This role the advantage of requiring only minor surgery, has never been proven in humans. However, allowing the achievement of normal blood sugar using gene-transfer techniques with a recombi- values with little surgical risk, there are still nant adenovirus, Kagami and colleagues30 demon- major limitations. Until about three years ago, strated that rat salivary glands, infected with this there had been only a few isolated successes with virus via intraductal retrograde infusion, were islet cell transplantation and then only for a short able to secrete human alpha1-antitrypsin directly period. Recent work has shown consistent success into the blood stream. By using in vivo gene- with islet transplantation in one group; patients transfer technology, this study reported that a in the study were infused through the portal vein mammalian salivary gland can secrete in an of the liver with beta cells isolated from human endocrine as well as in an exocrine manner (that cadaver pancreases.24 Studies are under way to confirm this success in other laboratories; how- Other studies showed a similar result following ever, it is difficult to obtain and purify islets.
the infection of rat salivary glands with a recom- At present, there are only 10,000 pancreases available for transplantation per year.25 Since it kallikrein, growth hormone and aquaporin-1, or currently takes two to three pancreases per trans- AQP1.31-33 AQP1 is the archetypal mammalian plantation, only approximately 3,000 to 5,000 water channel, and rats receiving AQP1 after patients could be treated per year. In addition, irradiation secreted saliva at control levels; this the process still requires the use of multiple approach may be useful for patients with salivary immunosuppressive agents. The risk of these hypofunction following head and neck irradiation drugs limits the use of this procedure to people for cancer, or for those with primary Sjögren’s who already have significant morbidity from their syndrome. These studies lend support to the notion that salivary glands may prove to be a immunotolerance not requiring drug therapy are useful target site for transgene delivery34-36 and, under way, along with research to find alterna- thus, for the therapeutic correction of some sys- temic single-protein-deficiency disorders The new field of stem cell research has focused including, potentially, insulin deficiency in on the provision of islet cells as one of its early goals. Human progenitor stem cells are pluripo-tential and thus capable of differentiating into a CONCLUSION
number of mature, functional cell types.27 For The American Diabetes Association has estab- example, under defined conditions in vitro, these lished criteria for testing undiagnosed people, and stem cells may be induced to differentiate into testing should be done more frequently in people fully functional, insulin-producing beta cells.
at high risk of developing the disease. The overall These cells could then be infused through the goal of diabetes management is to achieve a level portal vein into a patient who is profoundly of metabolic control that approaches that of the insulin-deficient (type 1 diabetes). Insulin- individual without diabetes, using target out- producing cells that previously were lost would be comes. Therapeutic approaches include the use of replaceable. Such an approach, known as thera- insulin, oral hypoglycemic agents and weight con- peutic cloning, will represent a significant trol. The dentist has an important role in refer- Copyright 2003 American Dental Association. All rights reserved.
ring patients with oral manifestations suggestive 12. Nature medicine. An alternative to Viagra? Available at: “www.nature.com/nm/web_specials/press/0101.html”. Accessed July 16, of diabetes to physicians for evaluation and treat- ment. The dentist also can recommend preven- 13. Lebovitz H. Oral therapies for diabetic hyperglycemia. Endocrinol tive, risk-reduction strategies to patients who 14. Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of may be more likely to develop diabetes, and metformin and rosiglitazone combination in patients with type 2 dia-betes mellitus: a randomized controlled trial. JAMA 2000;283:1695-702.
modify counterproductive attitudes toward oral 15. Ramlo-Halsted BA, Edelman SV. The natural history of type 2 dia- health care in those with diagnosed disease. Islet betes. Implications for clinical practice. Prim Care 1999;26(4):771-89.
16. Hirsch IB. Type 1 diabetes mellitus and the use of flexible insulin cell transplantation as a cure for diabetes is in its regimens. Am Fam Physician 1999;60:2343-56.
early clinical trials and a number of challenges 17. American Diabetes Association. Intensive diabetes management.
2nd ed. Alexandria, Va.: American Diabetes Association; 1998. remain. Therapeutic cloning may provide an 18. Skyler JS. Tactics for type 1 diabetes. Endocrinol Metab Clin alternate source of insulin-producing cells and 19. Farkas-Hirsch R, Hirsch IB. Continuous subcutaneous insulin thus a cure for diabetes. Gene-transfer techniques infusion: a review of the past and its implementation for the future.
using recombinant adenovirus may alternatively 20. Bode B. Establishing and verifying basal rates. In: Fredrickson L, provide another site (that is, the salivary gland) ed. The insulin pump therapy book: Insights from the experts. Sylmar, for the production and secretion of insulin. These 21. Type 2 diabetes in children and adolescents. American Diabetes techniques have not yet been applied in human Association. Diabetes Care 2000;23:381-9.
clinical trials, but their potential is exciting.
22. Moore PA, Orchard T, Guggenheimer J, Weyant RJ. Diabetes and oral health promotion: a survey of disease prevention behaviors. JADA2000;131:1333-41.
Ms. Robertson is the associate director, New York Diabetes Program, 23. Gruessner A, Sutherland DER. Pancreas transplants for the 345 E. 37th St., New York, N.Y. 10016, e-mail “nydiabetes@aol.com”.
United States (US) and non-US cases as reported to the International Address reprint requests to Ms. Robertson.
Pancreas Registry (IPTR) and to the United Network for OrganSharing (UNOS) In: Cecka JM, Terasaki PI, eds. Clinical transplants Dr. Drexler is a clinical assistant professor of medicine, New York 1997. Los Angeles: UCLA Tissue Typing Laboratory; 1998.
24. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free Dr. Vernillo is a professor, Department of Oral Pathology, Division of immunosuppressive regimen. N Engl J Med 2000;343(4):230-8.
Biological Science, Medicine and Surgery, New York University College 25. Robertson RP, Davis C, Larsen J, Stratta R, Sutherland DE. Pan- creas and islet transplantation for patients with diabetes. DiabetesCare 2000;23(1):112-6. 1. American Diabetes Association. Standards of medical care for 26. Robertson RP, Holohan TV, Genuth S. Therapeutic controversy: patients with diabetes mellitus. Diabetes Care 2003;26(1):S33-50.
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27. National Institutes of Health Stem Cell Task Force. Imple- 3. The effect of intensive treatment of diabetes on the development menting stem cell research. Available at: “www.nih.gov/news/ and progression of long-term complications in insulin-dependent dia- stemcell/022802implement.htm”. Accessed Aug. 7, 2003.
betes mellitus. Diabetes Control and Complications Trial Research 28. Baum BJ, Wang S, Cukierman E, et al. Re-engineering the func- Group. N Engl J Med 1993;329:977-86.
tions of a terminally differentiated epithelial cell in vivo. Ann N Y Acad 4. Intensive blood-glucose control with sulphonylureas or insulin com- pared with conventional treatment and risk of complications in 29. Lawrence AM, Tan S, Hojvat S, Kirsteins L. Salivary gland hyper- patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes glycemic factor: an extrapancreatic source of glucagon-like material.
Study Group (UKPDS). [published correction appears in Lancet 1998;352:1557]. Lancet 1998;352:837-53.
30. Kagami H, O’ Connell BC, Baum BJ. Evidence for the systemic 5. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with delivery of a transgene product from salivary glands. Hum Gene Ther macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-12.
31. Murakami H, Yayama K, Chao L, Chao J. Human kallikrein gene 6. American Association of Clinical Endocrinologist and the American delivery protects against gentamycin-induced nephrotoxicity in rats.
College of Endocrinology. Medical guidelines for the management of diabetes mellitus: the AACE system of intensive diabetes self-manage- 32. He X, Goldsmith CM, Marmary Y, et al. Systemic action of human ment—2002 update. Endocr Pract 2002;8(supplement 1):41-82.
growth hormone following adenovirus-mediated gene transfer to rat 7. Franz MJ, Bantle JP, Beebe CA, et al. Evidence-based nutrition submandibular glands. Gene Ther 1998;5:537-41.
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34. Baum BJ, O’Connell BC. The impact of gene therapy on dentistry.
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35. Baum BJ, Goldsmith CM, Hoque AT, et al. Salivary glands as a 10. Inzucchi SE. Oral hypoglycemic therapy for type 2 diabetes: scien- model for craniofacial applications of gene transfer. Int J Oral Max- 11. Glucophage prescribing information 2003. Princeton, N.J.: 36. Baum BJ, O’Connell BC. In vivo gene transfer to salivary glands.
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Copyright 2003 American Dental Association. All rights reserved.

Source: http://www.jada.info/cgi/reprint/134/suppl_1/16S.pdf