Diabetes Mellitus: More than Just Type 1 and 2 Brandon Nathan, MD Associate Professor University of Minnesota
Objectives 1. Recall three components of the beta cell that are important etiologies for monogenic forms of diabetes 2. List two therapeutic options for neonatal diabetes and maturity onset diabetes of young 3. Discuss the important diabetes educational topics for managing patients with cystic fibrosis related diabetes, hemochromatosis, or pancreatogenic diabetes
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Figure courtesy of Beta Cell Biology Consortium
Other Monogenic
Polygenic (T2D, T1D)
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Case • 2 month old, term infant with history of Intrauterine growth retardation (IUGR), unable to gain weight with increasing spitting up • BG level 460 mg/dl • What form of diabetes does this infant have?
Neonatal Diabetes Characteristics • Diabetes occurring in infants less than 6 months • Incidence 1 per 100,000‐500,000 births • Clinical Features • • • •
History of IUGR Failure to Thrive (FTT) Polyuria, dehydration DKA
• Transient or permanent (50%) • Variety of single gene mutations associated with either transient or permanent forms.
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K+‐ATP channel complex is basis for most common form of permanent neonatal diabetes
Therapy for permanent neonatal diabetes may include sulfonylureas • Insulin is the mainstay of therapy for these patients • However, in patients with KCNJ11 mutations (and ABCC8), adequate control of BG levels can be achieved with glyburide
Pearson EW, et.al. New Engl J Med, 2006
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Vignette #2 • 24 year old male who has a urinalysis performed as part of routine pre‐op visit, positive for glucose • Returns for fasting glucose and HbA1c: • BG 138 mg/dl (fasting), HbA1c 6.7%
• Family history • Mother with diabetes (lean) treated with metformin, A1c 6.5% • Maternal grandfather with diabetes (died at 85, no DM complications)
• Physical Exam • BMI 22 • No acanthosis nigricans
What is this patient’s diagnosis?
Maturity Onset of Diabetes in Young (MODY) • Group of disorders that stem from single gene mutations resulting in variable degree of insulin deficiency • Mutations in 13 different genes have now been identified that result in diabetes • 4 forms are most common: HNF1, GCK, HNF4 , HNF1 • Each form has variable course and features that may distinguish themselves
• Absent T1D autoantibodies • Characterized by unexpected or spurious finding of hyperglycemia (asymptomatic) or more significant hyperglycemia with polyuria/polydipsia and rarely DKA • Significant overlap in features of either type 1 or type 2 diabetes and thus is commonly misdiagnosed • Often family history of 1st degree family member with diabetes • Accounts for 1‐2% of all individuals diagnosed with diabetes
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Glucokinase
Bell GI and Polonsky KS. Nature, 2001
Normal Beta Cell Function
www.medbio.info
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HNF1 (MODY3) • Most common form of MODY (30‐70% of cases) • Transcription factor for regulating transcription of insulin and other genes in pancreas (GLUT2,PK) • Plays role in beta cell mass • Progressive hyperglycemia over time • Micro and macrovascular complications described • Often responds to sulfonylurea
GCK (MODY2) • 2nd most common form (30‐70% of cases) • Inactivating mutation in glucokinase • “glucose sensor” of the cell • Mild fasting BG levels and postprandial hyperglycemia • No complications or treatment needed • Homozygous mutations result in severe neonatal diabetes mellitus
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HNF4 (MODY1) • Orphan nuclear receptor • Important to gene expression and insulin secretion • 5‐10% of cases of MODY • Often managed with sulfonylurea
HNF1 (MODY5) • Transcription factor for regulating transcription of insulin • Renal cysts and other renal abnormalities • 5‐10% of all cases • Reproductive abnormalities
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IPF1 (MODY4) • Mutations in insulin promoter factor 1 homeobox • Transcription factor important in pancreatic development and a number of other beta‐cell specific genes. • 80% of those with severe genotypes
Diabetes Screening: OGTT • The OGTT, performed when the patient is clinically stable, is the test of choice for routine screening. • Poor performance of other tests • Correlates with important outcomes and response to treatment • Recommended annually for CF patients not already known to have diabetes. • OGTT screening should begin at least by age 10 years
Slide courtesy of Antoinette Moran, MD
CFRD – Monitoring after diagnosis • Monitoring after diagnosis of CFRD is made is a critical component of care delivery • Patients should test BG at home a minimum of four times daily, similar to other patients requiring insulin • Periods of illness, infection, stress often result in higher BG levels so it is important to test frequently during this time and adjust insulin dosing • HbA1c levels run lower in CF patients
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Cystic fibrosis‐related Type 2 diabetes diabetes Primarily insulin Primarily insulin resistance with variable insufficiency, with features of insulin insulin insufficiency resistance Absent Present Rare Rare Common Common but milder
Feature Underlying pathophysiology
Type 1 diabetes Insulin deficiency
Exocrine deficiency Risk for ketoacidosis Risk for microvascular complications Treatment
Absent Common Common Insulin only
Diet, oral hypoglycemic Insulin only agents, glucagon‐like peptide‐1 agonists, insulin
Dietary guidelines
Well‐balanced diet, account for carbohydrate consumption
Lower calorie, balanced diet with limited carbohydrate consumption
High calorie, well‐ balanced diet, account for carbohydrate consumption
CFRD Management Goals Maintain optimal nutrition status
Control hyperglycemia
CFRD
Facilitate adaptation to living with CFRD
Avoid severe hypoglycemia
Slide courtesy of Antoinette Moran, MD
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Insulin Secretion in Response to 4 Weeks of Ivacaftor Treatment
Pt 1: established CFRD with FH Pt 2: newly diagnosed CFRD without FH
www.medlibes.com
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Hemochromatosis • 1 in 200 individuals of N. European descent • “Bronze diabetes”: cirrhosis, skin pigmentation, diabetes • Diabetes prevalence 7‐40% • Variability due to disease severity, gene mutation
• Predominant defect is insulin secretory deficiency though increased insulin resistance also plays role. • Some studies have indicated additional increased IR among T2D patients with higher iron levels. • No calls for general screening unless + fam. History
• Tx: Phlebotomy and Insulin
Hemochromatosis
Diabetologia (2006) 49: 1661–1669
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Diabetes imparts significant mortality risk in Hemochromatosis population
N Engl J Med 1985; 313:1256‐1262
Pancreatitis • Inflammation of the pancreas most commonly related to alcohol use, biliary tract disease, trauma, drugs, or congenital abnormality • Accounts for 0.5‐1 % of all cases of diabetes in Western world, but up to 10% of cases in select populations (Southeast Asia) • In patients with chronic pancreatitis, 25‐80% will develop diabetes
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Pancreatitis related diabetes • Diabetes results from combination of insulin deficiency, pancreatic polypeptide deficiency, and hepatic insulin resistance • Diabetes is highly erratic, with fluctuating periods of hyperglycemia and hypoglycemia. • Tight glycemic control often very difficult to achieve • Treatment options similar to those for T2D • • • •
Lifestyle modification Metformin Sulfonylureas at early stage Insulin in select population
• Increased risk for pancreatic cancer (Metformin can reduce risk)
Other Unique Populations at Risk for Diabetes • Mitochondrial Disease • Transplant Patients • Endocrine Tumors • Acromegaly, Cushing Syndrome, Glucagonoma, Pheochromocytoma
• Patients on particular medication regimens • Glucocorticoids/Immunosuppressives • Dose, potency, tacrolimus>sirolimus
• Atypical antipsychotics • clozapine, olanzapine > risperidone
• Beta‐blockers • Statins • HIV anti‐retrovirals
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Summary • Monogenic forms of diabetes represent a small but very important group of disorders • Increased understanding of beta cell biology has led to our ability to detect such disorders and implement alternative therapies including sulfonylureas (or no therapy – MODY2) • Many forms of systemic disease are associated with an increased risk for non‐immune, atypical diabetes mellitus • Identification and management critical to disease outcomes
• Education of critical importance in counseling for correct medication, monitoring for progression of disease, and lifestyle modification for many of these disorders.
Q1. A child diagnosed with diabetes before the age of 2 is considered to have neonatal diabetes mellitus and should have genetic testing. 50%
50%
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Fa lse
Tr u
e
A. True B. False
Q2. Some forms of neonatal diabetes and MODY can be successfully managed with which class of oral diabetes medications? 25% 25% 25% 25% A. B. C. D.
Biguanide (metformin) DPP‐4 inhibitor Sulfonylurea Thiazolidenedione
A.
B.
C.
D.
Q3. Patients with MODY2(glucokinase mutation) should be educated on which of the following therapies? 20% 20% 20% 20% A. B. C. D. E.
20%
Insulin Metformin Sulfonylureas Thiazolidendiones None of the above A.
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B.
C.
D.
E.
Q4. Which of the following in NOT an important part of the therapeutic plan for a patient with CFRD? 25%
A. B. C. D.
25%
25%
25%
Home glucose monitoring Hypoglycemia avoidance Insulin Limiting caloric intake
A.
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B.
C.
D.
