Regarding Diabetes mellitus (DM)

Regarding Diabetes mellitus (DM) answer the following questions :

1. What are the clinical manifestations of DM?
2. What are the major types of DM and what are their distinguishing features?
3. What are the major acute and chronic complications of the disease?
4. What aspects of the medical history require special emphasis?
5. What aspects of the physical examination require special attention?
6. What laboratory tests are essential in the evaluation of the patient with suspected diabetes?
7. What are the goals of diabetes therapy and what treatment modalities are available? How should these be individualized?

Answers And Discussion
1. What are the clinical manifestations of DM?
DM is a complex metabolic disorder characterized by abnormalities of carbohydrate, lipid, and protein metabolism resulting either from a deficiency of insulin or from target tissue resistance to its cellular metabolic effects. It is the most common endocrine-metabolic disorder and affects an estimated 22 million people in the United States, with the incidence of new cases increasing by more than 700,000 per year.
Diabetes is manifested by the finding of hyperglycemia and the time dependent development of chronic complications (retinopathy, neuropathy, nephropathy, and accelerated atherosclerosis) resulting from the multiple metabolic derangements. Accordingly, the presenting clinical signs and
symptoms can be due to hyperglycemia or the complications of the disease, or both. In general, the major classic symptoms of polydipsia, polyuria, weight loss, and fatigue are found in the setting of new -onset diabetes in young patients whose disease is due to insulin deficiency .
On the other hand, older patients with diabetes may be relatively free of symptoms for a long time. In such patients, the diabetes is first detected either incidentally or because one of its chronic complications is discovered.
It is estimated that approximately one third of all the adult cases of diabetes in the United States remain undiagnosed.



2. What are the major types of DM and what are their distinguishing features?
The current classification (according to the National Diabetes Data Group) of DM and other categories of glucose intolerance consists of three clinical classes:

1. DM which includes type 1 diabetes mellitus (T1DM), [previously insulin-dependent diabetes mellitus (IDDM) or juvenile onset diabetes], and type 2 diabetes mellitus (T2DM), [previously non–insulin-dependent diabetes mellitus (NIDDM)]; 
2. impaired glucose tolerance/impaired fasting glucose; and 
3. gestational DM. 

Of these, Type 1 DM and Type 2 DM represent the largest category and are discussed here in further detail.

Impaired glucose tolerance and impaired fasting glucose are defined as an abnormality in glucose levels intermediate between normal and overt diabetes.

Gestational DM is defined as carbohydrate intolerance with onset or first recognition during pregnancy.

Type 1 DM constitutes approximately 5% to 10% of all cases of diabetes and is due to insulin deficiency resulting from the autoimmune destruction of insulin producing pancreatic islet cells. Therefore, such patients are prone to ketoacidosis and are absolutely dependent on exogenous insulin to sustain life (hence the term insulin-dependent diabetes). The onset in these patients is relatively abrupt and occurs usually in youth (mean age, 12 years), although it may arise at any age and is often misdiagnosed in adults.

Type 2 DM accounts for approximately 90% to 95% of all cases of diabetes. These patients have a dual impairment of insulin resistance (decreased target organ response to insulin, i.e., decreased glucose transport to muscle or ineffective suppression of hepatic glucose output) and inadequate insulin secretion to compensate for the insulin resistance. The recent obesity explosion, which is related to sedentary lifestyle and increased food intake, has exaggerated insulin resistance in susceptible people and contributed to the diabetes epidemic. There is usually a strong family history of DM in patients developing Type 2 DM in youth.

3. What are the major acute and chronic complications of the disease?
DKA, hyperglycemic, hyperosmolar, nonketotic coma (HHNKC), and hypoglycemia are the major acute complications of DM.

DKA is most commonly a complication of Type 1 DM and is initiated by an absolute or relative insulin deficiency and an increase in counter regulatory hormones (glucagon, epinephrine), leading to the hepatic overproduction of glucose and ketone bodies.

HHNKC is characterized by the insidious development of marked hyperglycemia, hyperosmolarity, dehydration, and prerenal azotemia in the absence of significant hyperketonemia or acidosis. Finally, hypoglycemia can occur as an acute complication of the therapy of both Type 1 DM and Type 2 DM, and is the most common acute life-threatening complication of diabetes. It is most common with intensive insulin therapy, and recurrent hypoglycemia can induce a condition known as hypoglycemia unawareness, a blunting of the adrenergic and neuroglycopenic signs and symptoms of hypoglycemia. The risk of hypoglycemia unawareness can be minimized and existing unawareness treated by strict avoidance of hypoglycemia.

The most common chronic complication of diabetes and the leading cause of death for people with diabetes is cardiovascular (CV) disease. Seventy seven percent of all hospitalizations and 80% of all mortality in diabetes is secondary to CV disease. Diabetes is an independent risk factor for CV disease. The incidence of CV events is so high in subjects w ith diabetes that diabetes is considered a CV risk equivalent. CV disease includes myocardial ischemia, stroke, and peripheral vascular disease. People with diabetes also have an increased incidence of heart failure, which will not be addressed in this section, as the pathophysiology is poorly understood. Outcomes after acute myocardial infarction (MI) in people with diabetes are worse than controls, but can be improved with intensive glycemic control in the hospital.
Interventional studies demonstrate that lipid lowering significantly decreases mortality and CV events in people with diabetes. In fact, it appears that people with DM may benefit from statins regardless of initial low -density lipoprotein (LDL). Additional large prospective trials demonstrate decreased
CV mortality with intensive BP control. There is no compelling data that improvement of glycemic control affects CV morbidity or mortality except in subjects with Type 1 DM.

Microvascular complications (retinopathy, nephropathy and neuropathy) are specific to diabetes and are related directly to poor glycemic control with a smaller contribution from hypertension and dyslipidemia.

Diabetes is the leading cause of blindness in the United States. By 10 years' duration of
diabetes, approximately 90% of individuals will have some degree of retinopathy. Retinopathy is largely a preventable complication of diabetes. Annual ophthalmologic examinations permit identification of individuals with progressive retinopathy.


Diabetes is the leading cause of renal failure/dialysis and transplantation nation wide. Forty percent to 60% of individuals with Type 1 DM and 10% to 30% of individuals with Type 2 DM will develop microalbuminuria, proteinuria, and end stage renal disease secondary to diabetes. Hypertension and glycemic control are the primary factors that promote progression of nephropathy in people with diabetes. Normalization of BP and glucose dramatically slow the progression from incipient nephropathy (detectable microalbumin) to overt nephropathy. All people with DM should have a BP lower than 130/80 mm Hg, preferably much lower. Aggressive control of hyperglycemia (with intensive therapy) and BP [with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers] has been shown to retard the progression of nephropathy in patients with DM.

Neuropathy is a common complication of diabetes affecting more than 50% of patients with time. The most common form of nerve injury in diabetes is distal symmetric polyneuropathy, which occurs in a stocking-glove distribution; it can be painless or painful. This type of neuropathy increases the risk for traumatic foot injury and amputation. Other forms of neuropathy include: autonomic neuropathy (associated with an increased risk of CV death and hypoglycemia unawareness); mononeuritis multiplex (a vascular occlusion to a single nerve distribution that w ill typically recover with time); and diabetic amyotrophy (a profound, uncommon demyelinating neuromuscular w asting syndrome).

Diabetes is also associated with impaired blood flow and sensation to the extremities. This leads to a high incidence of mechanical trauma and infectious complications, leading to amputation and hospitalization. Diabetes is the most frequent cause of non traumatic lower limb amputations. Each
year, more than 56,200 amputations are performed among people with diabetes. This complication is largely preventable by appropriate foot wear, regular foot examination, and education.

4. What aspects of the medical history require special emphasis?
A comprehensive medical history in a patient with suspected diabetes should be directed not only toward confirming the diagnosis but should also be used to review the nature of previous treatment programs and diabetes education, family history, the degree of past and recent glycemic control, and history of acute and chronic complications. Patients should also be queried about their dietary, weight, and exercise history.
Current medications for the management of diabetes, as well as other medications that may affect
glycemic control, should be recorded.
In addition, the presence, severity, and treatment of the acute and chronic complications of diabetes should be reviewed, including sexual function and dental care.
All patients should have a careful history for diabetic health care maintenance documented at each
visit. This includes glycemic control, lipid management (LDL <100, or <70 in high risk or known CV disease), BP management (<130/80 mm Hg), eye examination (annual), foot examination (each visit), diet, exercise, and self management

5. What aspects of the physical examination require special attention?
The vital signs are critical for patients with diabetes. BP greater than 130/80 mm Hg increases the risk for all complications, resting tachycardia suggests autonomic nervous system dysfunction, and weight gain or loss provides valuable information on severity of illness and adherence to therapy.
On physical examination, dentition is important as periodontal disease can impact glycemic control and is a risk factor for atherosclerosis (chronic inflammation).
Complete CV examination [including bruits and ankle brachial index (ABI)] and evaluation for edema can detect CV disease and heart failure. Loss of respiratory variation in heart rate is an early warning of autonomic neuropathy.
Foot examination, including pulses and monofilament testing, can identify high-risk feet and prevent amputations.
The retinal examination [undilated by a primary care physician (PCP)] is not sensitive for detection of retinopathy and needs to be done by an ophthalmologist or by using retinal photographs. It may be conducted by the PCP, but the needed formal annual evaluation should also be arranged.

6. What laboratory tests are essential in the evaluation of the patient with suspected diabetes?
The American Diabetes Association (ADA) and regulatory agencies have established standards for laboratory evaluation of diabetes.

The diagnosis of diabetes is formally made on the basis of one of the following criteria:

• fasting glucose 126 mg/dL or more on two occasions, 
• random glucose 200 mg/dL or more on two occasions, or 
• one abnormal reading as above together with symptoms consistent with diabetes (polyuria, nocturia, polydipsia, weight loss, blurred vision). 

Hemoglobin AIc (HbA Ic ) is not yet recommended as a diagnostic test because of a lack of standardization of existing assays, but is increasingly being considered by the ADA and regulatory agencies as a potential diagnostic tool.

7. What are the goals of diabetes therapy and what treatment modalities are available? How should these be individualized?
In general, the goals of diabetes therapy are

• to alleviate the signs and symptoms of the disease (e.g., polydipsia, polyuria, and nocturia); 
• to prevent the acute complications (i.e., hypoglycemia, DKA, and HHNKC); and
• to prevent the long-term complications of the disease (i.e., retinopathy, nephropathy, neuropathy, and atherosclerotic CV disease). 

Intensive glycemic control is now routine with HbAIc goals of 6.5% to 7%.

Insulin is required for glycemic control in Type 1 DM whereas Type 2 DM requires a multifaceted approach.

Diet and exercise are the mainstays of Type 2 DM therapy. They should be instituted first and patient adherence encouraged and maximized. Regardless of the ultimate regimen, diet and exercise remain
important.

Oral sulfonylurea agents that enhance β-cell insulin secretion, metformin that decreases hepatic glucose output, or thiazolidinediones that enhance insulin action in the periphery are added to this treatment if diet and exercise alone fail to control hyperglycemia optimally. These agents can also
be used in combination because they have different mechanisms and their actions are additive. Combination therapy with multiple classes of drugs is effective, but cost and monitoring for toxicity can be prohibitive.

With increased duration of Type 2 DM, β-cell mass and function are diminished and lead to relative
insulin insufficiency. At some point, insulin therapy becomes necessary for optimal glycemic control. In fact, insulin therapy is the best way to normalize glucose in patients not responding well to oral agents and should be employed as soon as glucose rises and not as a last resort.

New injectable agents that regulate glucagon, gastric emptying, satiety and insulin secretion: amylin and glucagon-like peptide-1 (GLP-1) agonists are recent additions to the list of anti-hyperglycemic agents. The most recent addition(s) are oral inhibitors of dipeptidyl peptidase 4 (DPP4), the enzyme
that inactivates GLP-1. These agents are currently used by providers specializing in diabetes.