Diabetes I: Beyond Gestational DM

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What is diabetes?

  • Diabetes is a Greek word meaning siphon - to pass through.

    • Mellitus, which is the common form we think of, is a Latin word meaning “sweet.” 

    • Insipidus, which is another form of diabetes we won’t talk about today, is a Latin word meaning “tasteless.” 

      • These terms refer to the effect of the disease on the urine, where mellitus is the passage of glucose through urine, making it sweet; while insipidus is unregulated water passing through urine, making it dilute.

  • Diabetes mellitus:

    • Around 8.8% of the world’s population has diabetes mellitus.

    • There are two main types.

      • Type 1 DM: this refers to a deficiency of insulin (10-15% of those with DM)

      • Type 2 DM: this refers to a resistance to insulin (85-90% of those with DM)

Type 1 Diabetes 

  • Insulin deficiency 

    • Thought to be primarily related to an autoimmune process leading to loss of pancreatic beta-cells.

  • Previously referred to as “juvenile diabetes” owing to predilection for onset in childhood:

    • 90,000 children diagnosed each year worldwide

    • Most common form of diabetes in those under age 15

      • Peak incidence at 12-14 years of age.

  • Has geographic predilection for Scandinavia, Europe, North America, and Australia. Incidence:

    • Over 10/100k in Europe, Russia, USA, Canada, Australia

    • Relatively rare in Asia - China, India, Middle East all <5/100k

  • Clinical onset of diabetes is marked by hallmark symptoms, and these are ultimate reason for diagnosis in >95% of cases:

    • Polydipsia (increased thirst)

    • Polyuria (increased urination)

    • Weight loss

    • Abdominal pain

    • Ketoacidosis (previous podcast!)

  • Given the insulin deficiency, treatment revolves around replacement of insulin with synthetic forms.

    • No successful studies thus far with immunologic interventions or preventive therapies.

Type 2 Diabetes

  • Acquired insulin resistance

    • This operates in three ways of pathophysiology:

      • Peripheral tissue insulin resistance: 

        • Overactivation of peripheral insulin receptors leads to downregulation - tissues are overextended.

      • Pancreatic beta cell dysfunction: 

        • Beta cells churning out loads of insulin - they get tired and “wear out.” 

      • Pancreatic alpha cell function increasing:

        • Hypothesized that the bar for hypoglycemia is raised physiologically - so inappropriate, early secretion of glucagon keeping blood sugars high.

    • T2DM’s insulin resistance is similar to gestational diabetes mellitus, where secretion of human placental lactogen creates an adaptogenic resistance to insulin (increasing glucose availability from the fetal perspective).

  • T2DM has a high prevalence worldwide, and is increasing.

    • A global pandemic of metabolic disease?!

      • Some estimate over 590 million worldwide will be affected by 2035.

      • Increasing prevalence worldwide, but most notable in US, Asia-Pacific, North Africa.

    • Highly associated with obesity - 90% of patients are obese or overweight at diagnosis.

      • Excess energy consumption combined with insufficient energy expenditure.

      • Generally adult-onset, but increasing prevalence in younger populations particularly with comorbid obesity.

  • Clinical onset is not typically acute:

    • Prediabetes often is manifest in these patients before diagnosis

      • 5-10% progress from prediabetes to T2DM annually.

      • Can be manifest for years-decade before progression.

    • Can manifest with similar acute symptoms to T1DM, but is most commonly insidious.

      • May be diagnosed incidentally with other healthcare-seeking, particularly major metabolic disease events (MI, stroke) or in seeking unrelated care (i.e., surgeries).

      • Common less acute presentations can include:

        • Fatigue, malaise

        • Infections (i.e., recurring genitourinary candidiasis)

        • Blurred vision

Some other, rarer forms of diabetes mellitus:

  • Latent autoimmune diabetes in adults (LADA) - a special type of DM that shares features with T1 and T2DM

    • Some may refer to this as “type 1.5” because of the mixed features:

      • Does not require insulin therapy for the first six months after diagnosis.

      • Typically acquired after age 35

      • Autoimmunity of T1DM - identifiable autoantibodies against pancreatic beta cells.

    • Depending on the stage in which they are identified or treated in their disease course, they may be responsive to oral insulin-sensitizing medications, or may require insulin.

  • Maturity Onset Diabetes of the Young (MODY) - hereditary form of DM with disruption of insulin production.

    • Typically an autosomal dominant inheritance:

      • Affected individuals have a 50% chance of passing to offspring.

    • Depending on the affected gene, hyperglycemia may be mild or severe, and treatment depends on which form of MODY a patient has.

    • Must be diagnosed before age 25.

  • Cystic fibrosis associated diabetes - given the failure of the exocrine pancreas in CF, most patients will develop a T1DM-like diabetes over time.

    • As therapies have gotten better for CF, some patients also develop T2DM features.

  • Steroid-associated diabetes - given hyperglycemia-inducing effects, those on chronic steroid therapy can develop diabetes akin to type 2 diabetes.

Diagnosing Diabetes Mellitus

  • Type 1 and type 2 diabetes 

    • Diagnosed according to the same ADA criteria for diabetes - one or more of:

      • Fasting glucose of > 126 mg/dL (with fasting defined as no caloric intake for at least 8 hours).

      • Glucose of > 200 mg/dL on a 2 hour, 75g oral glucose tolerance test (OGTT).

      • Hemoglobin A1c of > 6.5%.

      • Random glucose of > 200 mg/dL in a patient with classic hyperglycemia symptoms.

  • Prediabetes 

    • Diagnosed with any of the following:

      • Hemoglobin A1c of 5.7 - 6.4%.

      • Glucose of 140-199 mg/dL on a 2 hour, 75g OGTT.

      • Fasting glucose of 100-125 mg/dL

Complications of Diabetes

  • Acute

  • Chronic

    • Most of the major complications of diabetes that we think about result from chronic disease.

    • Many of the complications are due to microangiopathy, or damage to smallest blood vessels.

      • Excess blood glucose likely leads to incorporation of the excess sugar within capillary basement membranes.

      • This incorporation of excess sugar weakens the basement membranes, making them prone to micro-aneurysms.

      • When the microaneurysms rupture, new vessels and connective tissue must form, which causes sclerosis and narrowing of the arterioles surrounding the capillary.

      • This overall leads to worsened tissue perfusion and tissue function, and ultimately systemic hypertension.

    • Microangiopathy shows up everywhere:

      • Nephropathy

        • Damage to the renal glomeruli (capillaries of the kidney involved in filtration) worsen their filtering ability → glucosuria → microalbuminuria → CKD, renal failure, dialysis.

      • Neuropathy

        • Damage to the small vessels leading to nerve endings ultimately starves them of oxygen, impairing sensation.

          • This tends to develop in a “stocking and glove” form, affecting most distal extremities (smallest capillaries).

      • Retinopathy

        • Damage to small vessels in the retina, with growth of poor quality small new blood vessels (proliferative retinopathy) → macular edema → blindness 

          • Diabetic retinopathy is the most common cause of blindness among non-elderly adults in the world.

      • Sexual and reproductive dysfunction

        • Damage to small vessels leads to decreased sensation in women (and erectile dysfunction in men).

        • Infertility is more prevalent in patients with type 1 diabetes.

        • PCOS / oligo-ovulatory states are linked with insulin resistance and diabetes.

      • Encephalopathy

        • Linkage of diabetes and microvascular changes in the brain to cognitive decline, dementia.

    • Ultimately, this microangiopathy will contribute to the development of macroangiopathy, affecting larger blood vessels and complications such as:

      • Coronary artery disease → angina, myocardial infarction

      • Peripheral vascular disease → claudication, diabetic foot → amputation

      • Ischemic strokes

      • Hypertension

Diabetic Ketoacidosis for the OB/GYN

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What is DKA?

  • Diabetic ketoacidosis is a metabolic derangement affecting primarily patients with type 1 diabetes mellitus:

    • Typically in response to some sort of stress, an insulin deficiency is encountered

      • Because of the insulin deficiency, glucose cannot be taken up and metabolized → hyperglycemia.

      • Starvation hormone pathways activate, increasing lipolysis in the liver → free fatty acids → ketosis and acidosis.

      • The liver also doesn’t have insulin to effect uptake of excess glucose, and actually begins a process of proteolysis and gluconeogenesis → worsening ketosis and hyperglycemia. 

      • The hyperglycemia will lead to glucosuria (loss of glucose via the urine), and will cause a further loss of free water and electrolytes → ultimately progressing to impaired renal function. 

  • DKA may also occur in a patient with type 2 diabetes, where a severe relative insulin deficiency precipitates DKA or a related condition known as hyperosmolar hyperglycemic state (HHS). 

Diagnosis of DKA

  • T1DM with a precipitating event that may cause metabolic derangement and difficulty with giving insulin therapy:

    • Infections or other acute major illness

    • A new diagnosis of T1DM

    • Non-use (accidental or purposeful) of prescribed insulin therapy

    • Use of drugs which may affect carbohydrate metabolism: steroids, terbutaline, 2nd generation atypical antipsychotic agents

    • Cocaine use

    • Malfunction of insulin pumps - less common with newer systems, but still an important contributor!

  • Presentation is usually rapid onset, <24 hours:

    • Neurologic changes - confusion, stupor, coma, seizures

    • Abdominal pain - nausea, vomiting

    • Signs of volume depletion - tachycardia, dry mucous membranes, hypotension

    • “Fruity odor” due to exhaled acetone

    • “Kussmaul respirations” in severely affected patients - compensatory hyperventilation 

  • Laboratory evaluation:

    • CBC

    • BMP, with anion gap calculation

      • DKA with the production of ketones will produce an anion-gap metabolic acidosis (more on that momentarily)

      • Pseudohyponatremia is often present: correct the Na value (Na concentration falls by 2 mEq/L for each 100 mg/mL increase in glucose)

      • Potassium: will often be normal on serum values, but DKA represents a state of significant relative potassium deficit due to urinary losses and shifting of potassium extracellularly with insulin deficiency

        • When insulin is replaced, potassium is driven back into cells and will lower serum potassium - so must be replaced alongside insulin therapy! 

    • UA/ketones

    • Serum ketones / beta hydroxybutyrate 

    • Urine and serum osmolality

    • ABG - especially if serum bicarbonate is very low, or hypoxia is noted

      • On a VBG or ABG - you’ll see low pH with low bicarbonate value → metabolic acidosis

        • Remember in pregnancy, bicarbonate is typically a little lower due to compensation for chronic respiratory alkalosis -- so be sure to look at that value closely! 

    • Investigation of underlying cause -- ie., cultures/imaging if infection suspected; A1c to assess control over time; amylase/lipase if pancreatitis suspected

Treatment of DKA

Important: most large institutions will have a DKA protocol! Check your institution’s policies/procedures and note that in some places, ICU admission will be required for various levels of DKA. We present some pearls here:

Two primary things to do:

  • 1) Correction of fluid and electrolyte abnormalities

    • Give isotonic fluid (LR or NS) to replete extracellular volume losses and stabilize cardiovascular status.

      • If in shock, will need rapid bolusing.

      • If hypovolemic but not in shock, often start with 15-20 ml/kg lean body weight per hour for a few hours, before slowing down. 

      • If euvolemic, slower fluid infusion as clinically indicated. 

        • Most protocols will call for NS as the primary fluid -- however, the chloride load of NS may actually worsen acidosis initially! 

          • Two RCTs (only one mentioned in the podcast) have been performed in adults comparing LR to NS -- finding LR had a mild trend towards faster improvement, but there were no major differences otherwise. 

          • We bring this up as that trend towards faster improvement of acidosis in pregnancy may be of particular consideration - a faster improvement of pH may improve fetal appearance on monitoring. 

    • Fluid choice is often dictated by electrolyte concentrations:

    • Potassium should also be administered as the deficit will often be present:

      • If K < 3.3, KCl should be given at 20-40 mEq/hr, often added to the saline

      • If K 3.3 - 5.3, KCl 20-30 mEq is added to each liter of fluid ongoing

      • If K > 5.3, potassium does not need to be repleted (yet). 

        • Frequent monitoring of K is required, and may often in the initial stages need to be checked on an hourly basis.  

    • Other electrolytes can be in deficit, particularly phosphate and bicarbonate. However, these should not be directly repleted in most circumstances, with the exception of the most critically ill patients. 

  • 2) Administer insulin

    • IV insulin should be given for all patients alongside potassium repletion as we already described.

      • Remember - K may look normal on the BMP, but often is in deficit!

    • Short acting insulins (aspart, lispro, or regular) are preferred at the outset; long-acting insulins should be held until patient is more stable.

      • In mod-severe disease, often start with IV bolus of regular insulin at 0.1 u/kg, followed within five minutes by an infusion of 0.1u/kg/hr. 

        • Again -- most institutions have protocols that will calculate this out for you and prevent errors in administration! 

        • The effect of these doses are to bring serum glucose down 50-70 mg/dL per hour, which is usually about as fast as it can go!

        • Once glucose is around 200 mg/dL, insulin infusion should decrease to 0.02-0.05 u/kg/hr and fluids for repletion should switch to a dextrose-containing product. 

          • If glucose falls too rapidly below 200 mg/dL, can precipitate cerebral edema/injury. 

    • Once a patient is only in mild DKA or transitioning out of it, can add longer-acting agents back.

Other considerations for pregnancy:

  • Symptoms and treatment for pregnant folks are not different!

  • DKA is unfortunately more common in pregnancy, as: 

    • insulin requirements increase rapidly, predisposing patients more often to potential deficiencies

    • There are more opportunities for decompensation: n/v early pregnancy, food aversions, preterm labor, use of steroids for FLM, UTI/pyelonephritis, social concern for “harming baby” with insulin.

  • Recall normal pregnancy physiology is respiratory alkalosis -- so a pH of 7.36 may seem normal for most patients, but can represent significant acidosis in pregnancy!  

  • Consider LR for resuscitation of the pregnant patient: potentially faster improvement of pH in the first hour of treatment due to less chloride load. 

  • Consider tighter targets for glucose control with DKA (getting to 100-150 mg/dL, rather than 200, counterbalancing this with risk of cerebral edema from overcorrection). 

  • During acute DKA - fetal status is often not reassuring! 

    • If mom’s pH is 6.9, baby’s is the same or worse -- manifests with absent variability, decelerations.

    • May take several hours to resolve 

    • DKA alone is not an indication for delivery!

      • It’s preferred to try to resolve the metabolic derangements before proceeding with delivery - better maternal and fetal outcomes with waiting than proceeding with delivery with unstable maternal condition. 

Gestational Diabetes Trio, Featuring A Special Interview with Dr. Donald Coustan

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Happy Holidays to all, and to celebrate the season we have a very sweet triple episode release today! The first two episodes are focused on the pathophysiology, diagnosis, and treatment of GDM, while the third is a special interview with Dr. Donald Coustan, Professor and Chair Emeritus of the Department of Obstetrics and Gynecology at Brown University. Dr. Coustan was recently profiled by AJOG as a “Giant in Obstetrics and Gynecology.” We hope you enjoy the interview and his perspective on GDM and OB-GYN more generally.

The ACOG PB (PB 190) on GDM was recently updated in February 2018. There is also a new bulletin on Pregestational Diabetes (PB 201), though we don’t spend much time on pregestational diabetes today.

We discuss multiple ways to diagnose GDM, based on different organization’s recommendations. The classic Carpenter-Coustan criteria endorsed by ACOG and the National Diabetes Data Group (NDDG) are based on two-step testing. An initial 50 gram glucose tolerance test is performed, and patients move on to the second screen if their 1hr glucose is measured at 130-140 mg/dL, pending on the institution. It is generally accepted that a value >200 mg/dL is diagnostic without moving on to the second step.

The three hour test is based on a 100g glucose load. The cutoffs vary by time point. Two elevated values are needed to diagnose GDM; however, there is increased risk for the patient even with just one elevated value on three hour testing. The classic Carpenter-Coustan criteria as well as the NDDG criteria are shown here from PB 190:

ACOG PB 190: The Carpenter-Coustan criteria are the most commonly used in the USA.

There is also single-step testing proposed by the International Association for the Study of Diabetes in Pregnancy, that uses a 75g, two-hour glucose tolerance test. Any one elevated value (fasting > 92, 1 hour > 180, or 2 hour > 153) is diagnostic of GDM, and no second screen is needed. The ADA has endorsed these criteria recently but also admits that there is not clear-cut evidence to support one screening strategy over another. ACOG endorses the two-step screening at this time.

Much of the research regarding treatment of GDM that we review in the podcast is well-reviewed in PB 190, so we won’t rehash it here. If non-pharmacologic treatments fail (monitored fasting and postprandial blood glucose levels are consistently elevated), an oral agent or insulin is required, with insulin being the gold-standard. How do you initiate insulin? See our guide below!

And remember — postpartum patients with GDM need a 2 hour, 75 gram glucose tolerance test between 4 and 12 weeks postpartum to rule out type 2 diabetes. A fasting > 125 or a 2 hour > 200 is diagnostic. A fasting between 100-125 or a 2 hour between 140-199 demonstrates impaired glucose tolerance. And even with normal values, anyone with GDM has a 15-70% chance of developing T2DM later in life, so it’s an important part of the pregnancy history to correspond back to the patient’s PCP.