This page will provide a somewhat detailed overview of diabetes, including an understanding of insulin and its role in controlling various metabolic processes, including the regulation of blood sugar and the physiological and clinical consequences that result when there is inadequate insulin or there is resistance to it.

Introduction

If your dog or cat exhibits any or all of the following signs, it may have Diabetes mellitus:

  • Excessive thirst
  • Excessive urination
  • Ravenous Appetite
  • Weight loss

In some instances, e.g. a cat with acromegaly, there may actually be weight gain. In dogs with Diabetes mellitus, cataracts (clouding lenses of the eyes) may also develop, eventually resulting in blindness.

Disease Description

Diabetes mellitus usually refers to "dysfunction" in the amount, availability or biological activity of insulin normally secreted by ß-cells of the pancreas, ultimately resulting in excess levels of blood glucose (sugar) and other harmful metabolic derangements. This "dysfunction" can be absolute or it can be relative. (see Actions of Insulin, Insulin-resistance, Glucose Toxicity, below).

Insulin

Insulin is a hormone secreted from ß-cells of the pancreas (specifically, the portion called the Islets of Langerhans) ; its most notable function is to facilitate the uptake of glucose and other molecules by cells. Other Islet/pancreatic hormone types relevant to blood glucose control are glucagon (from the alpha-cells of Islets), somatastatin (from gamma Islet cells) and pancreatic polypeptide.

Factors affecting insulin secretion
In addition, there are non-pancreatic hormones and mediators that affect the secretion and/or the action of insulin. For a full appreciaton of blood sugar controls, it is not enough to appreciate just the role(s) of insulin alone; however, a more detailed account of the overall regulation of blood sugar is beyond the scope of this page.

Secretion of insulin is normally increased when blood sugar is high and decreased when when the blood sugar level is low, but there are other mitigating moderators of secretion and inhibition (see figure to the right). Physiological effects of insulin result when circulating insulin binds to cell surface receptors and are mediated by both changes at the cell surface and within cells ("intracellular"). The number of receptors (and hence, the effectiveness of insulin) decrease with obesity or excess circulating corticosteroid hormone(s).

See Insulin under treatment, below





Actions of Insulin

Insulin:

  1. Facilitates glucose uptake by muscle, fat, white blood cells, connective tissues, blood vessels and, notably, the glucagon-secreting cells of the pancreas, after binding to target-cell surface receptors
  2. Insulin is NOT required for glucose uptake by:
    1. the brain (except the satiety [hunger] center of the hypothalamus)
    2. parts of the kidney
    3. intestines
    4. red blood cells
    5. liver: glucose moves freely within the liver without insulin BUT the presence of insulin directs the liver to decrease production and release of glucose into the bloodstream and to increase production of glycogen (which is a storage product that can, if needed, be converted to glucose)
  3. Potassium and Phosphorus:
    1. insulin facilitates the movement of these electrolyes into cells
  4. Amino Acids (building blocks of protein) and Fatty Acids ( building blocks of fats):
    1. insulin enhances the transport and ultimately the synthesis of protein and fats
  5. Growth Promotion: by virtue of its protein synthesis promoting properties, insulin stimulates growth completely independent of its glucose transport property or other functions

See Insulin under treatment, below

Classification of Diabetes:

  1. Type 1: Type 1 Diabetes mellitus is characterized by a loss of functional ß-cells, ultimately resulting in a complete insulin deficiency.
  2. Type 2: In Type 2 Diabetes mellitus, cells normally responsive to the effects of insulin become resistant. The amount of insulin present may be normal, increased or decreased. Whether type 2 diabetes is applicable to veterinary patients is debatable, according to some endocrinologists, because almost always, veterinary patients require some form of insulin or other hypoglycemic agent to regulate the diabetes (i.e. diet alone does not suffice as it can in humans with type 2 diabetes, though there are reported incidences of cats going into remission when high protein, low carbohydrate diets are provided, in addition to insulin. As in humans with type 2 diabetes, obesity does play a role in the development of feline diabetes, however. ).
  3. IDDM*: (Insulin-Dependent-Diabetes Mellitus) refers to a clinical need for insulin therapy in the management of Diabetes mellitus. All Type 1 and some Type 2 patients require the administration of insulin to control metabolic abnormalities and clinical signs associated with the disease.
  4. NIDDM*: (Non-Insulin-Dependent-Diabetes mellitus) refers to a gradual or partial loss of ß-cell (insulin) activity and/or partial insulin-resistance, where treatment and control of clinical signs as well as metabolic derangements can be achieved without the addtion of insulin to the treatment regimen. Some type 2 diabetics are NIDDM.
  5. Additional Notes: Please be aware that ß-cell integrity and functionality may wax and wane; thus, patients (mostly cats) classified as NIDDM may become IDDM--or vice versa. There is no single test to a priori classify an incidence of Diabetes mellitus as IDDM or NIDDM.

Insulin Resistance and Glucose Toxicity

  1. Insulin resistance: refers to a subnormal response of susceptible cells to the physiological effect of normal amount of secreted insulin. This can occur at several levels at which insulin interacts with it's cellular target:
    1. Pre-receptor Level: When normal secretion of insulin occurs, it is possible that it's biological effect is thwarted before it reaches it's target receptor on the cell surface. This can occur via degradation or complexing of insulin molecules with antibodies in blood, rendering the insulin inactive.
    2. Receptor Level: There is an alteration ( decrease) in the specific affinity of a cell surface receptor for the the insulin molecule. Hence, insulin is less likely to bind to it; OR, there is a reduced number of receptors on the cell surface. This phenomenon of fewer receptors (known as "down-regulation") frequently occurs in obese animals or in the presence of excess counter-current (diabetogenic) hormones, such as glucagon, cortisol (or other corticosteroid), progesterone or thyroid hormone. In addition, down regulation of receptors occurs transiently in the presence of epinephrine ("adrenaline") such as can occur when an animal is stressed. Inflammation, such as from infection, can likewise increase counter-current hormone levels, such as cortisol and, at least in humans, causes hyperglucagonemia leading to insulin resistance. Glucagon activates glycogenolysis (breakdown of the carbohydrate storage product, glycogen) and gluconeogenesis (increased synthesis and release of glucose).
  2. Glucose Toxicity: Refers to decreased ability of ß-cells in the pancreas to release insulin in response to prolonged hyperglycemia (high blood sugar). The cells are exhausted and/or intoxicated by chronic hyperglycemia such that they do not respond normally. Glucose toxicity can be reversed in many instances provided glycemic control (e.g. treatment with insulin via injections) lowers blood sugar.

What's So Bad About Hyperglycemia?

Alterations in Hunger, Thirst and Urination

A relative or absolute insulin deficiency impairs the ability of insulin-dependent tissues to utilize glucose, amino acids (building blocks of proteins) and fatty acids (building blocks of fat). As the body becomes essentially "starved" (i.e. glucose is present but is unavailable to tissues) there is a "virtual" decrease in intracelluar glucose and the liver responds by synthesizing (and releasing into the blood) more glucose; this, in turn adds to the accumulated blood glucose load. At some level, the excess glucose "spills" into the urine dragging water molecules with it. Hence, fluid is lost and thirst increases to compensate for ensuing dehydration.

In addition, the appetite center in the brain (AKA the "satiety" center) is regulated by glucose influxes (this is the area of the brain that requires insulin for glucose uptake). With adequate glucose influx into this area of the brain (insulin dependent), hunger decreases; conversely, with decreased entry of glucose (e.g. as with Diabetes mellitus), hunger increases. Hence, in diabetic animals, increased appetite is a frequently observed clinical sign.

Weight Loss

In dealing with reduced availability of an energy substrate in Diabetes mellitus, and particularly in the absence of the positive modulatory effects of insulin on preventing muscle and fat breakdown ("catabolism") by the counter-current regulatory hormones |*|, there is a loss of muscle mass and body fat--a weight loss--even in the presence of an increased appetite.

Other Common Consequences
  1. Blindness due to cataracts (dogs)
    dog with cataracts
  2. Chronic recurring pancreatitis
  3. Recurrent Infections
    1. Urinary Tract
    2. Skin
    3. Respiratory
  4. Diabetic Neuropathy
    1. Neurological signs include apparent limb weakness, poor motor control, ataxia (staggering), depressed reflexes
    2. These are secondary to nerve cell alterations in structure and integrity and, possibly, alterations in the integrity of small blood vessels that supply these nerves.
      cat with pantigrade stance
    3. In cats, there is often a plantigrade stance...animals stand on their hocks instead of their toes. These signs may be reversible with good control of the diabetic state.

|*|These counter-current molecules are normally present to antagonize a sudden drop in blood glucose: some are hormones (corticosteroids, growth hormone, glucagon); epinephrine, a neurotransmitter, is also included in this group. All of these, in one way or another, facilitate an increase in blood glucose, either by increasing the synthesis and/or release of glucose from the liver (corticosteroids, growth hormone, epinephrine), reducing uptake of glucose by tissues (corticosteroids. Glucagon normally functions to store excess sugar in the liver when insulin is present, but in the absence of adeqaute insulin, and in the presence of corticosteroids or infection/inflammation, it functions in diametrical opposition , decreasing cellular uptake of glucose, and increasing release of glucose from the liver). Some sex/pregnancy hormones, e.g. progesterone, are also antagonistic to the effects of insulin.

Diabetic KetoAcidosis

Diabetic ketoacidosis is a less common, but serious sequelae to uncontrolled Diabetes mellitus. With the inability to utilize the glucose that is present and the ever-demanding need for energy and substrates for normal homeostasis (i.e. maintaining the status quo), the body resorts to the breakdown of protein and fat for energy (and to synthesize MORE glucose!). Some of the fat is converted to "ketones" and "ketoacids". Initially this is a positive attempt to overcome a metabolic hurdle (a needed energy source). Ketones and ketoacids can supply important energy needs, at least for the short term. However, with time, there is a shift in the blood constituents, and microenvironment, as the ability to "buffer" metabolic acid is overwhelmed and a non-physiological state ensues. Blood acidity increases, altering normal metabolism, and continued breakdown of fat and muscle exacerbates the existing derangements, adversely affecting levels and availability of magnesium, potassium and phosphorus . [Among other functions, these minerals are essential for the generation of energy and the conduction of electro-sensitive tissue (such as heart, muscle and nerve tissue). Without energy...well you can imagine that things can pretty much fall apart.]

sequens of events causing diabetic ketoacidosis

A desperate attempt to synthesize more glucose by the liver from fat and protein breakdown products (but of course the effort is futile without insulin) worsens the elevated blood glucose problem; at some level, glucose ...ultimately "spills" into the urine and drags water molecules with it. Water is thus lost along with important electrolytes and the liver continues to accumulate fat for metabolism to ketones and ketoacids, and the production of more glucose.

The net result of this is that the liver enlarges and is painful, the animal is sick from all the imbalances, including the toxins generated from inadequate processing of metabolic substrates, and vomiting, often protracted in nature, results. Taken together...the water losses through urine and through vomit... there is SEVERE dehydration and with dehydration of this magnitude, there is poor heart function, and poor circulation. The organs do not receive adequate oxygen and nutrition. Along with inadequate energy resources, the net result of this cascade of events results, ultimately in shock, then multiple organ failure (euphemistically referred to as MODS..."multiple organ dysfunction syndrome") and then, painfully, death.

Diagnosis of Uncomplicated Diabetes mellitus

Clinical Signs

  • Excess thirst and urination ("polydipsia" and "polyuria", respectively)
  • Increased appetite
  • Weight loss
  • Infections (somewhere..such as urinary tract, respiratory tract, skin)

Required Laboratory Findings

  • Persistent fasting hyperglycemia (high blood sugar) and glucosuria (glucose in the urine)
    • It is important to determine that hyperglycemia is not attributed to stress (e.g from a visit to the vet) or another spurious phenomenon
    • And that glucosuria is not attributed to kidney dysfunction (e.g. failure of the kidneys to re-absorb the glucose from the filtrate before producing the final urine product)
  • Elevated blood fructosamine or glycohemoglobin
    • These products reflect the average blood glucose levels over the past weeks or days and are therefore not significantly altered by momentary fluctuations due to transient stressors (such as a visit to the vet).

Other Possible Laboratory Results

  • Elevated liver enzymes and abnormal liver function tests
    • These are not always present but when seen may reflect underlying factors causing the diabetes (e.g. pancreatitis, primary liver disease, infection, neoplasia, inflammatory diseases, endocrine gland abberations)
    • OR they may the result of diabetes directly (diabetic hepatopathy)

Diagnosis of Complicated Diabetes mellitus

Additional Abnormalities and Laboratory Findings

Besides the laboratory findings above, other comorbidities may be present resulting in additional laboratory abnormalities. These include pancreatitis, hepatic lipidosis, diabetic ketoacidosis, infection (e.g. urinary tract infection)

  • Elevated pancreatic enzymes
  • Acid-base (pH) and electrolyte derangements, particularly sodium, potassium and phorphorus
  • Decreased thyroid hormone
  • Signs of renal (or other organ) dysfunction
  • Elevated lipids (fat) and cholesterol
  • Ketones (from anorexia if very sick...for whatever reason...or from diabetic ketoacidosis)

Treatment

Goals

  • Maintain blood glucose levels within the normal range both after and between meals
  • Attain or maintain normal body weight
  • Treat underlying cause(s) and concurrent exacerbating issue(s) (if known)

Dietary Management

Fiber (dogs)**
  • Purpose is to prevent wide fluctuations in blood sugar levels after meals ("post prandial")
    • Insoluble Fibers: work by shortening intestinal transit times (reducing the amount of time for glucose to be absorbed)
      • Wheat; wheat bran
      • Grains
      • Vegetables
      • Seed husks
      • Pumpkin (mixed fiber type)
    • Soluble Fibers: form a gel that actually decreases contact with the intestinal lining (where absorption occurs), and thus decreases absorption. They are also fermented. Fermentation by intestinal bacteria results in products that inhibit production and release of glucose and promote uptake and utilization of these by cells of intestinal lining. Examples:
      • Citrus
      • Pectin
      • Barley
      • Pectin
      • Vegetables
      • Guar gum
      • Pumpkin (mixed fiber type)

**NOTE: There is currently debate about whether all diabetic dogs are better managed on a high fiber diet or just a regular, adult-maintenance quality dog food that has moderate fiber. In addition dogs who are underweight should not be fed high fiber diets (it can contribute to further weight loss). And some dogs on a high fiber diet actually experience untoward gastrointestinal side effect, such as inappetance, flatulence and diarrhea, and may even experience a higher post-prandial (after meal) blood glucose values than desired.

Complex Carbohydrates (dog)
  • When digestable, complex carbohydrates are included (at greater than 50% on a dry weight basis) there is observed improvement in the control of post-prandial blood sugar levels
Protein (cats)
  • It appears that fiber and complex carbohydrates are much less important in cats than in dogs. In cats, a high protein diet, low carbohydrate diet such a kitten diet (e.g. Hills P/D or Purina-DM or Hills MD) is most beneficial in the controlling blood glucose levels
Feeding Recommendations
  • Dog
    • In the Underweight Dog
      • Use a highly palatable diet with moderate (5%-10%) or low (2%-5%) mixed soluble and insoluble fiber content
    • In the dog with Good Body Weight and Condition
      • Diet should contain moderate (5%-10%) to high (10%-15%) mixed soluble and insoluble fiber content (Some say that insoluble is better for glycemic control)
    • In the Overweight Dog
      • Use a high (10%-15%) mixed fiber, low fat diet with complex carbohydrates
      • Better control is attained with weight reduction (obesity is risk factor for onset of diabetes). Weight reduction will promote an increased number of insulin receptors AND better utilization of glucose by cells (after uptake via insulin!)
      • However, one may need to add some minerals, protein and a little fat with a high fiber diet because high fiber also reduces the digestability of protein and some minerals, and very low fat may reduce the absorption of certain vitamins.
  • Cat
    • In cats, it appears that fiber is much less important than in dogs
    • In cats, a high protein (animal protein) diet, low carbohydrate diet , such a kitten diet (e.g. Hills P/D or Purina-DM or Hills MD) is most beneficial
    • In general canned versions of these have less carbohydrate than kibble for the equivalent amount of protein
Other Dietary Considerations
  • In cats, there are instances where diabetic patients appear to go into full remission on diet, alone
  • Omega-3 Fatty Acid Supplementation
    • Omega-3 fatty acids...often helpful in controlling symptoms of allergy and certain inflammatory conditions should not necessarily be added to the diet of a diabetic animal; there is no known benefit in controlling blood sugar in diabetic dogs either. In fact, because they may increase blood sugar (as seen in some humans), one should evaluate the clinical benefit vs risk if omega-3 fatty acids are used in the diabetic dog where there are concurrent conditions responsive to omega-3 fatty acids.

Drugs

Oral Hypoglycemic Options
  • Most medications in this class require some functional ß-cells (e.g. in type2 diabetes)
    • Oral hypoglycemic agents are not routinely used in cats or dogs
      • Type 2 diabetes doesn't occur in the dog
      • Some cats initially present with type 2 diabetes
        • A small percentage of cats may respond if hyperglycemia is mild to moderate
        • Some of these drugs, e.g glipizide, may actually accelerate ß-cell (native insulin) loss
        • Certain drugs should not be given to obese animals (a large percentage of feline patients with diabetes)
        • One drug, acarbose, may be given with insulin to control post-prandial hyperglycemia, but there are freqently untoward side effects, such as diarrhea
  • Sulfonylureas are the most likely oral hypoglycemic to be tried in cats.
Insulin Therapy
Insulins and their properties

As shown in the table to the right, there are many different insulin types available. These differ in properties such as the onset of activity, duration of action and the magnitude of effect. Other factors may also influence these parameter, such as ongoing infection or inflammation, obesity, stress, concurrent medications and production of antibodies to one or another form of insulin. Here are some important considerations when choosing insulin therapy for diabetes.

Other Considerations
  • Expense:
    • Glucose curves:
      • To ascertain the correct dose for maximizing onset, duration and magnitude of effect of any given insulin in an individual animal, glucose curves...multiple glucose determinations thoughout the course of a day...will be necessary. They may need to be repeated at 7-10 day intervals until an optimal insulin type, dose and frequency of administration to control diabetes can be ascertained.
      • Glucose curves can be done in the home by the owner in some instance.
        • The results of the curve will be more representative of the animal's glucose control because the animal will not experience the stress of having to stay in the veterinary hospital (Stress --> increase blood glucose)
        • In home glucose testing will necessitate the purchase of a glucometer certified accurate for veterinary patients
      • It is not recommended to avoid doing glucose curves, because of the Somogyi Effect, which will be otherwise missed
        • If a spot blood glucose level is too high it could be because the dose of insulin is too high....OR...TOO LOW. The solution may not be to increase the insulin dose, but rather to decrease the insulin dose
          • If the insulin dose is too high, glucose will drop dramatically, and the liver will compensate by dumping excessive amount of stored glucose into the blood, which will show up when blood glucose is then measured
          • If the insulin dose is too low, glucose will not be transported into cells, and blood glucose levels will also appear to be high
    • Insulin:
      • The cost of different insulin types and brands can vary, but in recent years the prices have generally been on the increase.
      • As a rule, the expense will be greater for larger dogs, compared to small dogs and cats
    • Ancillary tests and procedures:
      • Urinalyses, urine cultures, antibiotics
        • Diabetic animals are prone to infections, especially urinary tract infections often requiring additional diagnostics, and treatment
      • Fructosamine: to help determine average glucose control over weeks
      • Timely dental cleaning: dental disease is risk factor for resistance to insulin; maintaining good dental health is essential to control diabetes in dogs and cats
    • Special diets: In some instances, special veterinary diets are needed to maximize control of blood glucose
    • Veterinary hospital visits: Where there are problems or complications (e.g. other illnesses including DKA) that may directly or indirectly affect glycemic control, the patient may need to undergo additional exams, diagnostics and treatments for these issues.
  • Time:
    • As you might have surmised by now, managing a diabetic pet, especially when there are complications, can be time and labor intensive
    • Continous monitoring for side effects, e.g. signs of hyPOglycemia, DKA etc., requires due diligence with frequent observation of the pet's behavior and attitude
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