I. Pathophysiology of Type I Diabetes
Diabetes mellitus comprises a diverse group of heterogeneous disorders which have hyperglycemia as a common manifestation. Increasing evidence is accruing that even mild degrees of hyperglycemia are associated with long-term complications and an increased risk of cardiovascular disease.
|Types of Diabetes Mellitus|
|Type||Pathophysiology||Age of onset/predictors|
|Type I (IDDM)||Autoimmune beta-cell destruction||Younger with 40% < 20
Can occur at any age, +FH
|Type II (NIDDM)||Multiple genes presumed
(none identified to date)
Obesity major risk factor
|Older; majority > 40; Gestational diabetes; obesity|
|MODY (maturity onset diabetes of the young)||Glucokinase gene mutations
in < 20%
|1st to 2nd decade; + FH|
|Type 1.5 DM||Unknown; not as insulin resistant at NIDDM||Increased in African-Americans|
Type I diabetes is an autoimmune disease with onset anytime between birth and the tenth decade. The incidence peaks in early adolescence. This form of diabetes represents less than 10% of the total population of individuals with diabetes but represents the best studied in regard to etiology and the effects of therapy and has a disproportionate effect on the expenditure of health care dollars going to treat diabetes and its complications. It is a progressive immunological disorder than can be diagnosed before overt pancreatic $ cell failure by identifying the presence of anti-islet cell antibodies, anti-insulin antibodies, antibodies against glutamic acid decarboxylase (GAD), and decreased early insulin release in response to an intravenous glucose challenge. The importance of recognizing this disorder early is the potential to intervene. Clinical trials now are being conducted to identify whether $ cell “rest” induced by low dose exogenous insulin therapy in nondiabetic individuals who are predicted to develop diabetes within 5 years will delay or prevent the onset of overt disease. Studies also are addressing the issue of oral insulin administration to induce immunological tolerance. There is a strong multigene contribution to the etiology of type I diabetes but the responsible genes have not been identified although some progress has been made in localizing their chromosomal positions. Type I diabetes places affected individuals at increased risk for premature death due to macrovascular complications and end-stage renal disease as well as to the consequences of blindness and peripheral and autonomic neuropathy. The primary goals of therapy are to preserve a normal life-style and to prevent complications before they occur.
The presentation of Type I diabetes varies from acute life-threatening ketoacidosis and hyperglycemia to a more insidious clinical course. It appears that the number of patients presenting with florid ketoacidosis is decreasing although ketoacidosis world-wide still is associated with a mortality rate ranging as high as 10%. Increasingly, patients are presenting with symptoms of polyuria and polydipsia or with fatigue thus making the distinction between early type I DM and type II DM more difficult by clinical presentation alone.
So-called type 1.5 diabetes is a relatively newly recognized group of patients with diabetes. Originally described by investigators from Florida, this group of patients included primarily young African-Americans. These individuals may present with mild diabetic ketoacidosis that is relatively easy to treat. Subsequently, they may be responsive to oral hypoglycemic agents. The etiology of this disorder is unclear. Another group of patients with characteristics distinct from those of the majority of patients with type II diabetes have been designated as patients with Flatbush diabetes. These patients are more insulin sensitive and more insulin deficient than the majority of patients with “classical” type II diabetes.
II. Complications associated with diabetes mellitus
A. Role of hyperglycemia per se:
There now is firm evidence that many of the complications associated with long-standing diabetes are related to hyperglycemia per se. The DCCT study unequivocally links glycemic control with microvascular complications. What is less clear are the mechanisms responsible for hyperglycemia-induced changes in major blood vessels (macrovascular disease), nerves (neuropathy), and other tissues. The importance of identifying the biochemical mechanisms responsible for these changes is critically important if new therapies directed at preventing complications can be developed. Hyperglycemia is associated with alterations of endothelial cells, smooth muscle cells, plasma lipid components (glycated and oxidized LDL), and platelets. Yet, no single mechanism is the cause for all of the complications of diabetes.
Advanced glycosylation end products (AGEs) increasingly are being recognized for the important role that they play in altering the structure and function of various tissues. Glycosylated hemoglobin is one example of an AGE that is used to assess integrated glycemic control over 4-6 weeks, Other AGEs include glycosylated basement membrane proteins and collagen. These proteins may have considerable pathophysiological significance both in regard to altering the structure of tissues but also for their ability to stimulate cytokines from local inflammatory cells that participate in the development of glycemia-related complications.
The polyol pathway (conversion of glucose ! sorbitol via the enzyme aldose reductase) is implicated in several complications of diabetes including the accelerated development of cataracts and the development of neuropathy. In the lens sorbitol accumulation may play a direct role in cataract development. In peripheral nerves, the depletion of myo-inositol due to activation of aldose reductase may play a significant role in the development of neuropathy. A number of studies support the notion that inhibition of aldose reductase may delay the onset of diabetic neuropathy. There is no evidence that any form of therapy can reverse structural changes in tissues that are correlated with the complications of diabetes. Clinical trials with potent aldose reductase inhibitors have been disappointing in regard to the clinical outcome but this may represent the late stage of complications at which treatment is initiated.
B. Role of hyperinsulinemia per se:
Hyperinsulinemia in the absence of hyperglycemia has been linked to hypertension, dyslipidemia, and premature cardiovascular disease in type II DM. While the data making these associations come primarily from epidemiological studies, some supportive data from animal models and human studies support these associations. This issue is important in Type I DM as well as in Type II DM, because in the former, peripheral administration of insulin produces systemic hyperinsulinemia relative to system insulin levels in normal subjects with a function beta cells.
Regardless of the specific biochemical mechanism underlying the following complications, patients with diabetes are at a dramatically increased risk for a number of micro- and macrovascular conditions compared to the non-diabetic population.
Complication Relative Risk
End-stage renal failure 25x
Myocardial infarction 2-5x
(Adapted from Nathan, NEJM 328:1676, 1993).
Approaches to the management of type I diabetes mellitus
A. DCCT results and implications: The Diabetes Control and Complications Trial (DCCT) was a large (1441 patients) prospective clinical trial that was directed at defining whether intensive insulin therapy could alter the development and/or progression of diabetes microvascular complications, specifically diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. Secondary outcome. variables included an assessment of the incidence of macrovascular disease. Intensive therapy was defined as three to four insulin injections daily (or an insulin pump) accompanying 4-7 daily measurements of blood glucose using a glucose reflectance meter at home. Conventional therapy was defined as two injections of insulin daily with a pattern of monitoring typical of the individual at the time of entry into the study. Originally designed to last 10 years, the study was stopped at the end of 9 years when ongoing data analysis revealed dramatic statistical benefit for the intensively-treated group compared to the group treated with conventional insulin therapy. Data are summarized in the Table and Graphs above and below.
Diabetes control in DCCT study.
|Endpoint||Conventional Insulin Therapy||Intensive Insulin Therapy|
|Mean blood glucose(mg/dl)||231 + 55||155 + 30|
Importantly, not only was there a statistically significant reduction in the onset of new retinopathy, in the progression of existing retinopathy, in the development of microalbuminuria, and in neuropathy, there also was evidence of a continuous occurrence or progression of these complications with increasing glycohemoglobin levels.
Thus, dramatic reductions in microvascular complications occurred with a reduction of glycosylated hemoglobin levels of approximately 1.5%. The risk of progression of proliferative retinopathy was directly related to the height of the glycosylated hemoglobin level.
These data suggest that any improvement of glycemic control in subjects with type I diabetes mellitus can reduce their risk of microvascular complications. Indeed, recent evidence suggests that for every 10% reduction in HbAlc, there is a 40% reduction in the risk of microvascular complications. In regard to macrovascular complications, the DCCT study was not sufficiently large or of sufficiently long duration to be able to evaluate the effect of intensive therapy and excellent glycemic control on macrovascular outcomes. However, the data suggest that these outcomes also are reduced in those individuals with the best glycemic control.
The major risk associated with intensive insulin therapy as applied according the DCCT protocol was the development of severe hypoglycemia. Indeed, there was a three-fold increased risk of severe hypoglycemia (loss of consciousness, requiring the assistance of medical personnel) in the intensively treated subjects. As seen in the accompanying figure, the risk of hypoglycemia was inversely related to the glycosylated hemoglobin level.
There are several important caveats to be learned from the DCCT study.
1) It is feasible to improve glycemic control in patients with type I diabetes
mellitus using frequent insulin injections (intensive therapy), frequent
monitoring of blood glucose, and close supervision by an experienced health
2) Improved glycemic control is associated with a reduced occurrence and a
delayed progression of microvascular complications.
3) There is a suggestion of decreased risk of macrovascular events with
improved glycemic control.
4) The decreased risk of complications is proportional to the improvement in
glycemic control as measured by declining glycohemoglobin levels.
5) Intensive insulin therapy is not without risk. There was a three-fold increase
in the incidence of serious hypoglycemia (loss of consciousness or episodes
requiring the intervention of medical personnel) in the intensively treated group.
6) Individuals with type I diabetes must be assessed for their willingness and
their ability to comply with intensive therapy regimens before initiating such
7) The results of this study are not necessarily applicable to the larger
population of individuals with type II diabetes (see below).
Who is a candidate for intensive insulin therapy and who is not? What are the limitations of current therapeutic tools and what new tools are on the horizon?
If intensive insulin therapy can reduce the risk of diabetes complications, how can we achieve such control and what are the actual goals for blood glucose and glycohemoglobin levels?
1.Candidates for intensive insulin therapy
Diabetes and pregnancy: type I and gestational diabetes. There is excellent correlation between the level of glycemic control during the first trimester and the incidence of major congenital malformations in babies of subjects with type I diabetes. Glycemic control also is correlated with birth weight (fetal macrosomia with less than ideal control) and the incidence of other perinatal complications including fetal lung immaturity, fetal hypoglycemia, fetal hypocalcemia, and fetal hyperbilirubinemia. Women with type I diabetes mellitus who are planning to conceive should be advised to diabetes control as near euglycemia as possible prior to conception. All pregnant women should be screened with an oral glucose load between weeks 24 and 28 of gestation. Women with blood glucose values greater than 140 mg/dl after an oral glucose load should undergo a formal glucose tolerance test. This is one of the few clear indications for the use of a glucose tolerance test.
Perioperative period for any diabetic patient. There is increasing evidence that improved glycemic control can reduce length of stay (LOS) after surgery and reduce the risk of secondary complications of the surgical procedure.
Stroke victims. Recent data demonstrate that diabetic patients suffering a cerebrovascular accident have an increased likelihood of permanent or more severe neurological impairment if hyperglycemia persists in the immediate post-stroke period.
Any adolescent or adult with type I DM who is capable of learning the principles of intensive insulin therapy and who can comply with a program of frequent home glucose monitoring and self-determined insulin dosage adjustment.
Contraindications for intensive insulin therapy (open loop system):
1. Diabetic autonomic neuropathy
2. Diabetic gastroparesis
3. Hypoglycemia unawareness and/or recurrent severe hypoglycemia
4. Seizure disorder
5. Active myocardial ischemia
6. Severe renal or liver disease
2. Goals of intensive diabetes therapy in type I diabetes
1. Fasting blood glucose between 80-130 mg/dl with tendency to the higher end of this range if night time hypoglycemia is a problem
2. One hour post-prandial blood glucoses < 180 mg/dl
3. Glycohemoglobin of 7-8%
4. Avoidance of severe and frequent hypoglycemia
5. Maintenance of normal life style
The above goals can only be achieved with an educated patient capable of adjusting insulin therapy according to alterations in meal and exercise patterns and monitoring of blood glucoses frequently enough to allow these changes to be made.
3. Requirements for intensive insulin therapy
a. Patient education (including education of patient’s family)
Education is life long and ongoing
b. Frequent home blood glucose monitoring
New devices are simple, accurate, relatively free from operator error, and capable of storing blood glucose values. Noninvasive meters are on the horizon but not yet reliable or routinely available.
Software is available to “download” glucose meters for “third party” assessment of patient’s control. This can be enormously helpful in patient education as well as in maintaining accurate records.
While glycohemoglobin or fructosamine levels provide an accurate assessment of overall glycemic control and target ranges for glycemic control, they do not provide sufficient information to allow adjustment of dietary, exercise, and insulin therapy. This can be achieved only by monitoring blood glucoses and adjusting insulin accordingly.
Fasting blood glucose daily; glucose before lunch and before supper to adjust insulin dose; BG at bedtime to avoid nocturnal hypoglycemia; occasional (1 x/week) BG at 3-4AM to test for asymptomatic hypoglycemia; occasional post-meal blood glucose.
c. Frequent insulin injections
As discussed below, the more frequent the injections, the better the ability to match insulin delivery with insulin needs. This allows greater freedom of life style and potentially reduces the risk of hypoglycemia. The goal is good mean blood glucose with a small excursion around that mean.
d. Frequent contacts with health care personnel
Periodic evaluation by physicians, diabetes nurse educators and less frequent but routine evaluations by nutritionists and exercise physiologists will help achieve and maintain good control. Assessment of the feet (for evaluation of neuropathy, blood flow or local nail or skin problems) and eyes (for retinopathy) should be performed at each visit. Patients with Type I DM of over 5 years duration should see an ophthalmologist yearly for evaluation of microvascular retinal disease. Urinary microalbumin should be measured yearly and recognized as a predictor of progressive renal insufficiency.
C. Health maintenance: reduction of secondary factors
1. Smoking accelerates micro- and macrovascular disease and should be
2. Hypertension accelerates micro- and macrovascular disease and should be treated aggressively. Thiazides should be avoided because of their effect on lipid metabolism. High dose beta adrenergic blockers should be avoided, if possible, because of their ability to blunt symptoms of hypoglycemia. Alpha blockers, calcium channel blockers, and ACE inhibitors are particularly useful.
3. The development of microscopic proteinuria has predictive power and therapeutic implications. Data are clear that the development of microscopic albuminuria (> 40 mg/24 hr) predicts with development of progressive renal insufficiency. The development of renal insufficiency can be delayed by instituting therapy with an angiotensin by instituting therapy with an angiotensin converting enzyme inhibitor (ACE inhibitor) even in the absence of hypertension. The largest clinical trial to date used Captopril as the ACE inhibitor but newer data suggest that other ACE inhibitors also may be effective. Currently, there are no data on angiotensin II receptor inhibitors but studies are underway.
D. Approaches to achieving intensive insulin therapy safely
1. Know your patient – diet, exercise, meal times, work schedule, life style
2. Know the kinetics of available insulins and how to use different insulins together.
a. The major limitation of current insulin therapy is the inability to match insulin needs with insulin absorption from the subcutaneous space. Even multiple insulin injections (4 times daily) do not completely overcome this limitation. The increased incidence of hypoglycemic reactions in patients treated with intensive insulin regimens comes from the inability to exactly match insulin absorption with insulin requirements. If one achieves good control of blood glucose 1-2 hours after a meal, it is likely that hypoglycemia may occur 3-4 hours after that meal. This situation is complicated further by the poor kinetic reproducibility of subcutaneous insulin preparations.
b. A short-acting insulin analog (Humalog?r>
c. Deciding on an insulin regimen for intensive insulin therapy
i. Adjust regimen to the goals of therapy and the life-style of the patient
ii. Options for intensive insulin therapy: The steps described below refer to increasing intensity or complexity of insulin therapy regimens. All are predicated on doing frequent home blood glucose monitoring to adjust insulin doses and to reduce the risk of hypoglycemia.
Stepped insulin therapy: Increasing intensity to achieve improved glycemic control
ieve improved glycemic control
|Step||AC Breakfast||AC Lunch||AC Supper||qHS|
|5||Continuous subcutaneous insulin infusion (CSII)- open loop|
|6||Continuous intravenous (intraperitoneal) insulin infusion pump|
|7||Segmental pancreatic or islet transplantation|
N.B. Lente insulin can be substituted for NPH insulin in any of these regimens recognizing that its kinetic pattern is slightly different. Lispro insulin can be substituted for regular insulin in the above regimens taking into account caveats described above.
V. Approaches to Diabetes Complications
A. General background
1. The biochemical etiology of diabetic microvascular complications is incompletely understood. Favored theories include the role of advanced glycosylation end products (AGEs) and depletion of intracellular myo-inositol. Glucosamine, a product of glucose metabolism also has been a favored mediator. Smooth muscle cell and endothelial cell proliferation as well as the effects of oxidized lipids and alterations of tissue thromoplastin activator also have been investigated for their role.
2. Improving glycemic control reduces the risk of complications.
3. Interfering with the formation of AGEs inhibits microvascular disease in animal models of diabetes and clinical trials are underway to investigate their role in human diabetes.
4. Prevention of diabetes complications can be accomplished through patient education and careful follow-up. Silent neuropathy and retinopathy should be anticipated, identified, and treated with local preventive measures.
B. Diabetic Nephropathy: various stages
1. Stage 1: increased GFR
2. Stage 2: Intermittent microalbuminuria (30-300 mg/24 hr)
3. Stage 3: Elevated albumin excretion rate at rest
4. Stage 4: Clinical nephropathy (>0.5 gm protein/24 hr)
5. Stage 5: End stage renal disease leading to dialysis/transplantation
ACE inhibition decreases transglomerular pressure and decreases microalbuminuria. It also retards the development of end-stage renal disease. This will be covered more completely in the section on renal disease.
C. Diabetic neuropathy: various clinical presentations
1. Peripheral sensory neuropathy: After 10-15 years duration of diabetes, the vast majority of patients have some degree of sensory nerve dysfunction in the lower extremities. Painful neuropathy occurs in a minority but can be very troublesome.
a. Rx of painful peripheral neuropathy can be accomplished first with local measures including capascasin ointment to deplete axonal Substance P.
b. Tricyclic antidepressants, dilantin, tegretol may be useful in some patients unresponsive to local rx.
c. Systemic analgesics should be avoided, if possible, because of their addictive potential.
2. Autonomic neuropathy: The most common manifestation is impotence in males although sexual dysfunction in females should always be included in the interim history. More severe autonomic dysfunction includes vascular instability, gastroparesis, intestinal motor dysfunction (small and large bowel), and arrythmias. Remember that autonomic neuropathy can predispose to asymptomatic hypoglycemia.
a. In patients with impotence, vascular and psychological factors also can play a significant role.
b. Severe gastroparesis and hypoglycemia unawareness are contraindications for intensive insulin therapy.
c. Treatment is symptomatic although newer agents for gastroparesis may be helpful including metochlopramide and cisapride.
3. Diabetic amyotrophy: Unusual condition presenting as marked weight loss, depression, and muscle weakness with atrophy in middle-aged men with diabetes (often Type II). Looks like cancer cachexia but often self-limited over 6-9 months. Some patients benefit from antidepressants.
4. Diabetic motor mononeuropathies: Most often involving cranial nerves III, IV, VI, or VII. These are vascular infarcts of the nerve and tend to improve spontaneously over 3-6 months. No clear indication that systemic steroids increase rate of recovery.
1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. NEJM 329:977, 1993.
2. Woodworth JR, Howey DC, Bowsher RR. Establishment of time-action profiles for regular and NPH insulin using pharmacodynamic modeling. Diabetes Care 17:64, 1994.
3. Galloway JA, Spradlin CT, Nelson RL, Wentworth SM, Davidson JA, Swarner JL. Factors influencing the absorption, serum insulin concentration, and blood glucose responses after injection of regular insulin and various insulin mixtures. Diabetes Care 4:366, 1981.
4. Brownlee M. Glycation and diabetic complications. Diabetes 43:836, 1994.
5. Lewis E J, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting enzyme inhibition on diabetic neuropathy. N Engl J Med 329:1456, 1993.
6. Nathan DM. Long-term complications of diabetes mellitus. N Engl J Med 328:1676, 1993.