Type 2 diabetes mellitus (DM) is a common disease affecting 30.3 million people, 9.4% of the US population. Of these, an estimated 7 million people are undiagnosed.
Type 2 DM typically has two pathophysiologic defects: an insulin secretory defect and insulin resistance. Symptoms of uncontrolled hyperglycemia include polyuria, polydipsia, blurry vision and possibly dehydration and weight loss. Patients may complain of thirst, sweet cravings, generalized fatigue, abdominal discomfort, and muscle cramps. They may have a history of poor wound healing and/or frequent infections. Basic metabolic laboratory tests may reveal a random blood glucose level over 200 mg/dL [11.1 mmol/L], hyper- or hyponatremia, hypokalemia, metabolic acid-base derangements and acute renal or pre-renal insufficiency. Historical clues for the diagnosis of type 2 DM might include pre-existing history of pre-diabetes, a family history of type 2 diabetes, an ethnicity at higher risk for DM (e.g. African-American, Hispanic, Native American, Pacific Islander), a history of gestational diabetes, obesity, and sedentary lifestyle.
HyperglycemiaInsulin resistance, insulin deficiency (pancreatic beta cell failure), increased gluconeogenesis, glycogenolysisDehydration, polyuria, polydipsiaOsmotic diuresis, compensatory thirstWeight loss, sweet cravingsGlycosuric calorie loss and inadequate glucose utilizationMuscle pain and abdominal discomfortLactic acid accumulation, hypokalemia, electrolyte /acid-base derangementsMetabolic alkalosis and/or acidosis, electrolyte disturbancesDehydration and ketogenesisKetogenesisInsulin deficiency resulting in lipolysis yielding free fatty acids, substrate for formation of ketone bodies
DIAGNOSIS AND DIFFERENTIAL
Diabetes can be diagnosed in several ways: 1) Presence of symptoms of hyperglycemia with a random plasma blood glucose of 200 mg/dL [11.1 mmol/L] or greater; 2) fasting blood glucose of 126 mg/dL [7.0 mmol/L], or higher on two occasions; 3) blood glucose of 200 mg/dL [11.1 mmol/L] or greater at 2 hours following the 75-gram oral glucose tolerance test (OGTT); 4) hemoglobin A1C value of 6.5% or greater. If asymptomatic, the diagnosis of diabetes is confirmed with two consecutive day abnormal results from the same test or with two different tests on the same day showing concordant results. If using the hemoglobin A1C for diagnosis, one should be aware of several conditions (some common) making this measure un-interpretable.
Adult patients with type 1 and type 2 DM can sometimes present similarly. If a patient presents with hyperglycemia, ketonemia and metabolic acidosis, distinguishing between types of diabetes is not necessary in this acute setting because initially both type 1 and type 2 DM are treated with insulin. Later the two diseases may be distinguished with antibody testing although this is neither completely sensitive nor specific. Type 2 DM can also present acutely with a hyperglycemic hyperosmolar state (HHS) with dehydration, altered level of consciousness, and a lesser degree of clinical ketosis than seen in diabetic ketoacidosis (DKA). Consideration for genetic syndromes and concomitant rare conditions of endocrine hormone excess (cortisol, growth hormone, epinephrine, glucagon) leading to hyperglycemia should be in the non-urgent setting for patients with new diagnoses of diabetes.
DIAGNOSTIC TESTS NEEDED AND SUGGESTED
For an acute presentation of diabetes with hyperglycemic symptoms, the patient should have a basic metabolic panel of laboratory tests including glucose, electrolytes, blood urea nitrogen, creatinine, blood and/or urinary ketones, liver function tests, and urinalysis. Other testing should be guided by a patient’s history and physical exam and might include evaluation for infection or cardiac dysfunction. A hemoglobin A1C reflects the average blood glucose over the last 90 days and is a helpful test. Distinguishing type 1 from type 2 DM can on occasions be difficult but can be assisted with the presence of circulating autoantibodies, including glutamic acid decarboxylase (GAD) 65 antibody, tyrosine phosphatase antibody (IA-2), and/or zinc transporter 8 (ZnT8) antibody. The presence of antibody suggests an autoimmune lesion as seen in type 1 DM. In type 1 DM insulin levels are characteristically low, whereas they may be normal or elevated at the onset of type 2 DM.
Insulin therapy is the initial management choice for patients presenting with hyperglycemia and catabolic symptoms including weight loss. If laboratory abnormalities suggest concurrent DKA or HHS, these must be treated emergently with aggressive saline rehydration, intravenous insulin, potassium and other electrolyte replacement according to protocols.
For a severely hyperglycemic patient, with a catabolic presentation that usually includes moderate to severe volume depletion, the first therapeutic step is rehydration, usually with intravenous saline. After adequate hydration, therapy with physiologic doses of insulin (0.3-0.4 units per kilogram body weight daily) is recommended. The ideal treatment regimen would be a combination of a long-acting basal insulin plus multiple premeal prandial “bolus” injections to manage meal-related insulin requirements and correction of pre-meal hyperglycemia, referred to as basal-bolus insulin therapy. A good starting place is to prescribe half the total daily insulin dose as basal and the other half as bolus. The combination of a long- or an intermediate-acting insulin (e.g. insulin glargine, insulin determir, insulin degludec, or insulin NPH) and a rapid acting analogue are good options for basal-bolus therapy. The basal dose is given as 1-2 separate injections from the bolus injections.
The premeal “bolus” dose is calculated by summing the dose required to cover the carbohydrate load plus the dose to correct premeal hyperglycemia and is given as one injection 10-15 minutes before the meal. Particularly with premeal hyperglycemia but even with mealtime glucose levels within target, today’s rapid-acting analogues require time for absorption to avoid more severe postprandial hyperglycemia (this is typically called the “lag time”). In an acute setting, and in a less sophisticated patient or a patient with economical concerns for paying for the more expensive insulin analogues, it might be more appropriate to begin therapy with a twice-daily pre-mixed insulin. Even though this regimen is not ideal for many for the long-term because it does not allow for sufficient dose titration, this regimen allows approximate physiologic basal-bolus insulin coverage with fewer injections. Nevertheless, if starting with basal-bolus or premixed insulin, it is best to teach the patient to use the strategy of correcting pre-meal hyperglycemia with an additional dose of rapid acting insulin analogue, given 10-15 minutes before the meal. This adds tremendous flexibility to an otherwise rigid regimen.
Until more education is possible, the need to limit high glycemic-load carbohydrate intake (such as with sweetened beverages and juice) should be strongly reinforced with counseling. Certainly, arrangements for general and dietary diabetes education should be made for a newly diagnosed diabetic patient or for a patient new to insulin therapy.
The patient will use a glucose meter to check his/her fasting and premeal blood glucose levels. For the patient on basal-bolus insulin therapy, s/he will increase bedtime basal insulin doses by 1-2 units every 3 days until fasting blood glucose falls into target range of 90 -130 mg/dL [5 – 7.2 mmol/L]. Ideally, bedtime and fasting glucose levels are about the same at the end of the basal insulin titration. If there is a consistent reduction in bedtime to fasting glucose by more than 50 mg/dL [2.8 mmol/L], basal insulin dose is too high.
Adjustments for pre-meal insulin doses are most easily made with an algorithm written clearly for the patient to reference. The importance of injecting the mealtime insulin 10 -15 minutes before eating needs to be emphasized. In contrast to type 1 diabetes where carbohydrate counting is standard, most patients with type 2 diabetes do well by taking the same mealtime dose or altering up or down based on the size of the meal. For example, one might take 8 units for a smaller meal and 12 units for a large one. If patients feel hypoglycemic symptoms (sweating, shaking, mental fogginess, hunger) despite concurrent blood glucoses levels in the normal range, one could use smaller insulin dose increments to lower blood glucose into the target range more gradually. Generally, increases of insulin dose by 10% are well tolerated by patients. Late night snacks without insulin coverage may lead to morning hyperglycemia and interfere with the assessment of the adequacy of the bedtime insulin doses. Correction doses are “trial and error,” but most patients with type 2 diabetes require an insulin sensitivity factor (ISF) of 30 (i.e., a 30 mg/dL in glucose reduction is expected from 1 unit of insulin injected). For example, if additional insulin is provided for premeal glucose levels above 150 mg/dL, 1 extra unit would be given for 150-180 mg/dL, 2 units for 181-210 mg/dL, etc. When starting insulin, it may be appropriate to use a more conservative insulin sensitivity factor such as 40 or 50.
Initial diabetes therapy includes counseling for lifestyle and diabetic nutritional interventions. In the absence of contraindications, starting therapy with metformin is recommended as an adjunctive therapy with insulin to reduce insulin requirements and minimize weight gain in patients with type 2 diabetes. In patients who have received long-term treatment with metformin and those with laboratory findings or symptoms consistent with anemia and/or peripheral neuropathy, measurement of vitamin B12 level is recommended, as long-term use of metformin is associated with vitamin B12 deficiency.
Transitioning from insulin to metformin and other non-insulin antihyperglycemic medications may be considered if the patient initially presented with an A1c <10% and if the patient is able to achieve a reasonable A1c goal that is corroborated by the SMBG data while using a total daily insulin dose that is low. This should be guided by a patient-centered approach, giving considerations to factors including drug efficacy relative to patient’s A1c, weight, risk of hypoglycemia, history of cardiovascular disease, side effect profiles, renal function, drug delivery method, and cost. Among the non-insulin antihyperglycemic medications, clinicians should be aware of the risk of DKA associated with the sodium-glucose cotransporter 2 (SGLT2) inhibitors, which provide insulin-independent glucose lowering by blocking the SGLT2’s glucose reabsorption in the proximal renal tubule. The SGLT2 inhibitors make an attractive therapeutic option given their cardioprotective, renoprotective, and weight loss properties. However, US FDA issued a warning about the risk of ketosis associated with this class of medications in 2015. In patients taking the SGLT2 inhibitors, ketosis may occur in the absence of significant hyperglycemia with a plasma glucose level <252mg/dl [<14 mmol/L], termed “euglycemic DKA.” However, “euglycemic DKA” may be misleading, as most cases of ketosis in type 2 diabetes associated with SGLT2 inhibitors exhibit significant or even severe hyperglycemia, owing to the action of the counter-regulatory glucagon resulting in the enhancement of hepatic gluconeogenesis, glycogen breakdown, and lipolysis. Clinicians should educate patients on SGLT2 inhibitors to immediately stop taking the medication and seek medical attention if they develop nausea, vomiting, abdominal pain, and dyspnea, as well as having their urine and serum for ketones promptly tested.
Total premeal insulin dose is sum of:Suggested UnitsMeal coverage5-8 units for smaller meal, 9-12 units for larger mealPre-meal hyperglycemia correction1 unit per 30-50 mg/dL above150 mg/dL
Subramanian S, Baidal D, Skyler JS, Hirsch IB. The Management of Type 1 Diabetes. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-2016 Nov 16.
Cavaiola TS, Pettus JH. Management Of Type 2 Diabetes: Selecting Amongst Available Pharmacological Agents. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-2017 Mar 31.
Gosmanov AR, Gosmanova EO, Kitabchi AE. Hyperglycemic Crises: Diabetic Ketoacidosis (DKA), And Hyperglycemic Hyperosmolar State (HHS). In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-2015 May 19.
Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. PMC free article
] [ PubMed
2011 Mar 16;
Rubinow KB, Hirsch IB. Reexamining metrics for glucose control.