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Introduction Insulin Basics Regulation Classification Insulin Resistance Clinical Signs-Effects Diabetic-Ketoacidosis Diagnosis Treatment Goals Diet Insulin Treatment Oral-Hypoglycemics

Introduction:

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

        Excess thirst
        Excess urination
        Ravenous Appetite
        Weight loss

      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 Insulin-resistance, Glucose Toxicity, and "More Basics..." below).

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Insulin Basics

Insulin is a hormone secreted from ß-cells of the pancreas (specifically, the portion called the Islets of Langerhans). 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. In addition, there are non-pancreatic hormones and mediators that affect the secretion and/or the action of insulin. For a full appreciaton blood sugar controls, it is not enough to appreciate just the role(s) of insulin; for a more detailed account of the overall regulation of blood sugar, please check the "More Basics....." link

Insulin:

Secretion is normally increased when blood sugar is high and decreased when low, but there are other mitigating moderators of secretion and inhibition (see "More Details....")

Effects result when insulin binds to cell surface receptors and are mediated by both changes at the cell surface and within cells ("intracellular")

The number of receptors decrease with obesity or excess circulating corticosteroid hormone(s)

Actions:

Facilitates glucose uptake by muscle, fat, white blood cells, connective tissues, blood vessels and, notably, the glucagon-secreting cells (see "More Detail....") of the pancreas, after binding to target-cell surface receptors
Insulin is NOT required for glucose uptake by:

brain (except the satiety [hunger] center of the hypothalamus)

parts of the kidney

intestines

red blood cells

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)

Potassium and Phosphorus: insulin facilitates the movement of these electrolyes into cells

Amino Acids (protein building blocks) and Fatty Acids (fat building blocks): insulin enhaces the transport and ultimately the synthesis of protein and fats

Growth Promotion: by virtue of its protein synthesis promoting properties, insulin stimulates growth completely independent of its transport or other functions.r

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More Detail About the Regulation of Blood Sugar

(click on the link above for a more detailed discussion)



    Classification:

      Type 1: Type 1 Diabetes mellitus is characterized by a loss of functional ß-cells, ultimately resulting in a complete insulin deficiency.

      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. As in humans with type 2 diabetes, obesity does play a role in the development of feline diabetes, however. ).

    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.

    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.

    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.
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    Insulin Resistance and Glucose Toxicity

    Insulin resistance: refers to a subnormal response of suseptible 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:

    Pre-receptor LevelWhen normal secretion of insulin occurs, it is possible that it's biolgical 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.

    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.

    Glucose Toxicity: Refers to decreased ability of ß-cells in the pancreas to release insulin in response to prolongued 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.

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    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 increased to compensate for ensuing dehydration.
    In addition, the appetite center in the brain (AKA the "satiety" center) is regulated by glucose influxes. 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 increased. 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-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

    Blindness due to cataracts (dogs)
    Chronic recurring pancreatitis
    Recurrent Infections
    Urinary Tract
    Skin
    Respiratory
    Diabetic Neuropathy
    Neurological signs include apparent limb weakness, poor motor control, ataxia (staggering), depressed reflexes; 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. 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.

    Diabetic KetoAcidosis (A VERY LARGE flow chart of events is here as toggle click)

    With the inability to utilize the glucose that is present and the ever-demanding need for energy and substates for normal homeostasis (i.e. maintaing 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 (an 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, adversly 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.]. 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 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, the liver continues to accumulate fat for metabolism to ketones and ketoacids, and more glucose; the liver enlarges and is painful, the animal is sick from all the imbalaces, 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 (euphamistically referred to as MODS..."multiple organ dysfunction syndrome"} and then, painfully, death.

Diagnosis

      Persistent fasting hyperglycemia (high blood sugar) and glucosuria (glucose in the urine)

        It is important to determine that hyperglycemia is not attributed to stress

      And that glucosuria is not attributed to kidney dysfunction (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 days or weeks and are therefore not significantly altered by momentary stressor (such as a visit to the vet)

    Clinical Signs

    Excess thirst and urination ("polydipsia" and "polyuria", respectively)

    Increased appetite

    Weight loss

    Infections (somewhere..such as urinary tract, respiratory tract, skin)

    Laboratory Results

    Hyperglycemia, glucosuria

    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 represent the consequences resulting from diabetes.

    Other abnormalities may be seen when there are complications, e.g. pancreatitis, diabetic ketoacidosis, infections, hepatic lipidosis. These include:

    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

    Urinalysis

    Glucosuria

    Urinary tract infection

    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 (if known)

    Dietary Management: Purpose is to prevent wide fluctuations in blood sugar levels after meals ("post prandial") by slowing and maintaining a steady-state rate of glucose absorption from the intestine. Increasing dietary fiber (especially the insoluble fiber) in dogs (but not cats!) may be beneficial in this regard

      Fiber Types (dogs only):

        Insoluble:

          Examples:

            Wheat; wheat bran
            Grains
            Vegetables
            Seed husks
            Pumpkin (mixed fiber type)

          Effects:

            Shorten intestinal transit time (less time to digest and absorb glucose)..BUT
            Decreases absorption of some vitamins and some minerals (e.g. zinc, chromium)

        Soluble:

          Examples:

            Citrus
            Pectin
            Barley
            Legumes
            Psillium
            Vegetables
            Guar gum
            Pumpkin (mixed fiber type)

          Effects:

            Decrease glucose absorption (forms gel that actually decreases contact with the intestinal lining (where absorption occurs), and thus decreases absorption)

            Is 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

            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

      Feeding Recommendations: These depend on body condition and species

        In cats, it appears that fiber is much less important than in dogs. In cats, a high protein diet , such a kitten diet (e.g. Hills P/D or Purina-DM or Hills MD) is most beneficial

        In the underweight dog:

          Use a highly palatable diet with moderate (5%-10%) or low (2%-5%) mixed soluble and insoluble fiber content

        In dog with good body condition and weight:

          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.

          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;unlike humans, where these have positive effects on the cardiovascular system, there is absolutely no such benefit in dogs, and no 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.

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    Insulin: 

      For NIDDM, dietary modification may be sufficient to control clinical signs of diabetes.
      Insulin injections are required for IDDM and certain instances of NIDDM where glucose toxicity and/or diabetic ketoacidosis has ensued.

      Sources: Insulin is derived from animal (beef, pork) or human recombinant gene sources; recently, Eli Lilly, a major producer of commercial insulin preparations, discontinued manufacture of many of the animal-derived insulins that were commonly employed in veterinary medicine.

      Types: Insulin comes as pure crytalline or as modifed to affect the rate of absorption and/or duration. Modification are usually via alteration of crystal size (e.g. Lente & Ultralente) and/or the addition of protamine zinc (e.g. PZI) or alterations in the acidity of the suspension (e.g. Glargine). Sometimes it is necessary to mix (or purchase pre-mixed) insulin types in order to obtain the desired onset and duration properties for a particular patient.

      Examples of types of insulin, and their properties are illustrated in the table, below.

Examples of Insulins
Type Route* Onset Max. Effect Duration of Effect
Dog Cat Dog Cat
Regular** IV Immediate
IM 10-30 min 1-4hr 1-4hr 3-8hr 3-8hr
SC 10-30min 1-5hr 1-5hr 4-10hr 4-10hr
NPH SC 0.5-3hr 2-10hr 2-8hr 4-24hr 4-12hr
Lente** SC <1 hr 2-10hr 2-8hr 6-24hr 6-14hr
Ultralente** SC 1-8hr 4-16hr 4-16hr 8-28hr 8-24hr
Humulin-N*** SC <-----------------Similar to NPH---------------->
Humulin-L*** SC <-----------------Similar to Lente---------------->
PZI SC 1-4hr 4-14hr 3-12hr 6-28hr 6-24hr
Glargine*** SC ? NA 4-12hr NA 8-14hr
      * (IV=intravenous; IM= intramuscular; SC= subcutaneous)
      ** human or animal source
      *** human

      Insulin Glargine, from Lantus, is a very long acting "peakless" insulin in humans, meaning that the results of a glucose curve (below) do not generally show the marked peaks and valleys of blood glucose values that change throughout the day on most other insulin regimens, but that glucose levels are more or less stable over a longer period of time. In some cats (but not in dogs) recently diagnosed with diabetes, the initial use of glargine, rather than one of the other insulin preparations, in conjunction with a high protein, low carbohydrate diet, can result in markedly reduced need for insulin. In a large number of these cases, cats may go into complete remission over the course of months on Glargine, and then no longer are diabetic!

      Monitor: After an initial 3-10 day treatment(sooner if insulin is glargine in cats), your veterinarian will probably wish to ascertain the effectiveness of the current insulin/diet treatment. This usually means:

        Serial bood sugar measurements (aka a "glucose curve")....usually blood sample is obtained hourly over 12-18 hours....to determine the best type and dose of insulin and frequency of administration. Sometimes several glucose curves separated by 10-14 days are required to achieve optimization of insulin type, dose and frequency, and to avoid the Somogyi phenomenon*.

        [* This refers to hyperglycemia resulting from too much insulin...where a transient hypoglycemia (from too much insulin) signals the countercurrent hormones to quickly increase blood sugar levels; this often results in overshooting normal blood sugar values...i.e. hyperglycemia.]

          Obtaining a glucose curve usually requires hospitalization and repeated pokes with a needle to obtain samples for measuring blood glucose levels.

          Hospitalization can be (and often is ) stressful for the patient; it is known that stress results in elevated blood cortisol and that circulating cortisol results in elevated blood sugar. Hence, getting an truly reflective sampling of a patient's response to insulin can be clouded by spurious effects of blood sugar levels that are the direct result of stress.

          It is now considered prudent to show clients how to perform a "glucose curve" at home...where it is relatively stress free, and where results are more reflective of "normal" for that particular patient. There are easy ways to obtain blood (e.g. usually from a tiny poke in an ear) from a patient and there are portable blood sugar determination devices that are suitable for owners and their animals. (download one of the movies about home testing cats to explain..Windows Media Player, Real Audio or Flash versions. The Real Audio is largest file...but easiest to view) There is information on-line about at-home glucose testing machines for dogs here

        Measure fasting blood sugar (glucose) in the morning before insulin administration

        Observe for changes in clinical signs, e.g. drinking and urination, appetitite, attitude, weight

        Additional blood testing and urinalysis (look for diabetogenic problems such as infections, and/or diseases of other endocrine glands)

    Oral Hypoglycemic Drugs

      In certain instances of type 2, NIDDM (most likely cats), where there are minimal clinical signs, and no concurrent illnesses, weight loss (may be obese!) or ketosis, oral hypoglycemic medications may be considered.

      Types:

        Sulfonylureas (e.g. Glucatrol®,glipizide, glimepiridine)

          MOA: increases insulin release (there must be some insulin-secreting ability) from the pancreas

          SIDE EFFECTS: liver toxicity, hypoglycemia, rash, amyloid (a harmful protein) deposition in the pancreas and subsequent exacerbation of pancreatic destruction. These drugs should not be used in the presence of reduced liver function.

        Biguanides (e.g. Metformin®, glucophage)

          MOA: inhibits glucose synthesis by the liver and increases the sensitivity of tissues to the action of insulin.

          SIDE EFFECTS: can not be used when there is concurrent kidney disease or impaired liver function.

        Thiozolidinediones (e.g. Rezulin®* (troglitazone), Avandia® (rosiglitazone))

          MOA: reduces insulin resistance...e.g. that caused by obesity...and enhances insulin actions in muscle, liver and fat tissues

          SIDE EFFECTS: appear to be relatively safe*; may be useful in preventing diabetes in obese animals (who are prone to insulin resistance).

          *Note: Rezulin® has recently been removed from the market because there are, in humans, some safety concerns; there are other like drugs that already exist (e.g. Avandia®) or will, doubtless, emerge and be applicable to veterinary medicine

        Acarbose (e.g. Precose®)

          MOA: slows the absorption (post-prandial) of glucose from the intestine and is most effective when patients exhibit persistent post-prandial hyperglycemia that is not responsive to dietary modification regimens.

          SIDE EFFECTS: gastrointestinal pain, gas (flatulence!), diarrhea

        Vanadium/Chromium (e.g. chromium picolate)

          MOA: supposedly increases sensitivity of tissues to insulin and decreases glucose release from the liver. Thes minerals are "naturally" present in tomatoes (canned?), pinapple, broccoli and white potatoes (the latter is also a good fiber source), and has been added to some commercial diets specifically designed for diabetic animals.

          SIDE EFFECTS: the chemistry is complex & inappropriate supplementation with these minerals can be toxic.

      More about Oral Hypoglycemics:

        The efficacy and safety of many oral hypoglycemic drugs for veterinary patients have not been completely established. Some of the early evidence suggests that single drugs or some combinations of these, with or without concurrent insulin administration, may be useful in the treatment of diabetic cats.

      Other Websites of Interest: An extensive amount of general information about diabetes in dogs and cats can be found here.

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