Type 2 Diabetes Mellitus

• Endocrine Case: Type 2 Diabetes (T2D)

Objectives

• Integrate basic science, population health, and clinical concepts using endocrine case presentations.

Patient Presentation: L.H.

• L.H. is a 43-year-old Mexican American female seeking a routine physical examination for a new job.
• Past medical history is significant for Gestational Diabetes Mellitus (GDM).
• L.H. has given birth to four children with birth weights of 7, 8.5, 10, and 11 pounds.
• She was told during her last pregnancy that she had "borderline diabetes."
• Family history includes type 2 diabetes (mother, maternal grandmother, older first cousin), hypertension, and cardiovascular disease (CVD).
• L.H. tries to walk 15 minutes twice a week.
• Physical examination reveals overweight (height 65 inches [165 cm], weight 165 pounds [74.8 kg], Body mass index (BMI) 28.3 kg/m²) and blood pressure of 145/85 mmHg.
• L.H. denies symptoms of polyphagia, polyuria, or lethargy.
• Electronic medical record documents hypertension and a fasting plasma glucose (FPG) value of 119 mg/dL measured 2 months prior.
• An A1c test ordered and results came back and reads 6.1%.

Risk Factors for Developing Type 2 Diabetes

• History of gestational diabetes.
• Family history of type 2 diabetes, hypertension, and CVD.
• Overweight status (BMI 28.3 kg/m²).
• Hypertension (BP 145/85 mm Hg).
• Elevated FPG in the recent history (119 mg/dL).

Criteria for Screening for Diabetes or Prediabetes in Asymptomatic Adults

• Testing should be considered in adults with overweight or obesity (BMI ≥25 kg/m² or ≥23 kg/m² in Asian American individuals) who have one or more of the following risk factors:
• A first-degree relative with diabetes.
• High-risk race and ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander).
• History of CVD.
• Hypertension (≥130/80 mmHg or on therapy for hypertension).
• HDL cholesterol level <35 mg/dL (<0.9 mmol/L) and/or a triglyceride level ≥250 mg/dL (>2.8 mmol/L).
• Individuals with polycystic ovary syndrome.
• Physical inactivity.
• Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans).
• People with prediabetes (A1C ≥5.7% [≥39 mmol/mol], impaired glucose tolerance (IGT), or impaired fasting glucose (IFG)) should be tested yearly.
• People diagnosed with GDM should have lifelong testing at least every 3 years.
• Testing should begin at age 35 years for all other people.
• Testing should be repeated at a minimum of 3-year intervals if results are normal, considering more frequent testing based on initial results and risk status.
• People with Human immunodeficiency virus (HIV), exposure to high-risk medicines, history of pancreatitis

Metabolic Abnormalities

• B-cell dysfunction, hyperinsulinemic compensation, and insulin resistance

Natural History of Untreated T2DM

• Hyperinsulinemic compensation happens because the pancreas secretes increasing amounts of insulin to compensate for insulin resistance and maintain normal glucose levels.
• Pre-diabetes and T2DM occur when the pancreas is unable to secrete sufficient insulin to compensate for insulin resistance.

Recommendations

• Weight loss and exercise were recommended.
• The rationale of weight loss is to increase insulin signaling in muscle, liver, and adipose tissue.
• The rationale of exercise is to increase GLUT4 translocation to the plasma membrane.
• Insulin stimulates muscle glucose uptake.
• Lipid-induced insulin resistance reduces muscle glucose uptake.
• Weight loss reduces FFA-induced insulin resistance.
• Weight loss and exercise improve muscle insulin sensitivity and glycemia.
• Weight loss (reduced adiposity) promotes insulin signaling.
• Acute exercise stimulates AMP-activated protein kinase (AMPK) activity and GLUT4 translocation.
• Increased glucose uptake means improved insulin sensitivity.
• Chronic exercise stimulates GLUT4 gene expression.

Two Years Later

• L.H. is now 45 with a height of 65 inches [165 cm], weight of 180 pounds [81.6 kg], and BMI of 30.9 kg/m².
  • The gynecologist noted glucosuria noticed during routine urinalysis.
• Two separate FPG of 150 and 167 mg/dL.
• A1c was 8.2%.
• L.H. reports lethargy and afternoon naps.
• Other medical problems are hypertension controlled by lisinopril 20 mg/day, and recurrent monilial infections (vaginal yeast) with fluconazole.
  • As a loan officer, she smokes a pack of cigarettes per day for 20 years, drinks occasional wine and at least two regular sodas daily and a "large" glass of orange juice every morning.
• LH has a sedentary lifestyle by only walking to her car.
• L.H. Given a diagnosis of type 2 diabetes.

Diagnoses

• Fasting laboratory assessment: glucose of 147 mg/dL and triglycerides of 250 mg/dL, total cholesterol (TC) of 250 mg/dL, HDL-cholesterol of 28 mg/dL, LDL-cholesterol of 152 mg/dL.

Metabolic Abnormalities

• B-cell dysfunction, absolute insulin deficiency, and insulin resistance.

Insulin Resistance

• Hyperglycemia is the most cause.

Regulation of Insulin Release

• Stimulants: Glucose, amino acids such as leucine, neural stimulation through acetylcholine, and sulfonlureas and meglitinides
• Amplifiers: Enteric hormones (glucagon-like peptide 1 (7-37) (GLP1), Gastric inhibitory peptide (GIP), Cholecystokinin, gastrin, and Secretin), Neural stimulation (ẞ-adrenergic effect of catecholamines for example), amino acids such as arginine, and GLP1 agonists
• Inhibitors: Neural stimulation (a-adrenergic effect of catecholamines), somatostatin, diazoxide, thiazides, ẞ-blockers, clonidine, phenytoin, vinblastine, colchicine

Likely Etiology of L.H.'s Recurrent Monilial Infections/Glucosuria

• High blood glucose levels lead to glucosuria, causing glucose to be excreted in the urine.
• Glucose-rich urine provides a favorable environment for fungal growth, such as Candida, leading to monilial infections.
• Kidney glucose reabsorption and the maximum threshold:
• Glucose is absorbed from the proximal tubule with the sodium-glucose cotransporters (SGLT2 and SGLT1)
• The maximum re-absorptive capacity determines the glucose threshold.
• TmG maximum tubular glucose reabsorptive capacity.
• The presence of glucose in urine will be shown when thresholds are exceeded: ~180 mg/dL.

Goal of A1c for L.H

• An A1C goal of <7% (<53 mmol/mol) is appropriate for many nonpregnant adults without severe or frequent hypoglycemia affecting health or quality of life.

Initial Management of L.H.

• Start with life changing advice and the administration of metformin.
• Decreased hepatic glucose production is the main indication for Metformin prescription.

Metformin

• Metformin inhibits Complex I of the electron transport chain.
• There is an increased [AMP]
• Elevated [AMP] directly suppresses gluconeogenesis through the inhibition of Fructose-1,6-bisphosphatase (FBP1), antagonizes glucagon action, and reduces lipid accumulation through increased AMPK activation.
• Metformin inhibits gluconeogenesis and improves hepatic insulin sensitivity

Metformin Prescription

• Metformin 500 mg twice daily (bid) with food, to increase dosage to 500 mg every morning and 1000 mg every evening after 1 week.
• Since taking Metformin, nausea and diarrhea were reported.
• Doses were skipped at times.
• Physicians should use a patient-centered approach to discuss patients' difficulties.
• The first step is in maximizing long-term medication adherence.

Additional Metformin Interventions

• Discuss treatment goals.
• Consider informing the patience of the effects of skipping doses before prescribing.

Later Symptoms

• Metformin options should be addressed, and the frequency of when glucose should be measured.
• The new lab tests you have ordered is: -Fast Glucose is 147 -Triglycerides is 250 -Total Cholesterol is 250 -HDL is 28 -LDL is 152

Abormalities

• High TC, low HDL, and high TG is consistent with diabetic dyslipidemia.

ASCVD Drug Class

• It would depend on the 10 year ASCVD risk, however a statin may be most useful in the management.
• Lipid Treatment goals: -Primary Prevention -Secondary Prevention. In order to improve blood glucose levels LH. had adopted new life habits and had some motivating factors.
• LH stopped drinking drinking regular sodas and juices but eats bread or two large tortillas at each meal.
• She has not been able to implement her walks three times weekly, she only walks once a week.
• FPG fell to 130 mg/dL, a majority of her postprandial BG levels were >180 mg/dL.
• A1c is currently 7.4%, and fasting triglyceride levels are now 199 mg/dL.

Therapy Adjustment

• It is necessary to include other pharmacological interventions, such as GLP-1 receptor agonist.

Semaglutide

• She declined after hearing. of SGLT2 inhibitors' effects.
• GLP effects include glucose insulin secretion, and also inhibit glucagon. GLP can also prevent of low blood sugar levels.
• Other considerations include delayed gastric emptying.

Side Effects of GLP-1 Receptor Agonists

• Nausea, vomiting, diarrhea, increased risk of developing pancreatitis, increased risk for thyroid C-cell tumors and gastroparesis
• FDA drugs may be linked to pancreatitis.
• Hypoglycemia, nausea 44 %, vomiting 13 % and diarrhea 13 %

Semaglutide Agonists

• They delay gastric emptying hence it should be avoided in patients with gastroparesis
• Two years go by, it becomes visible that The patients chief complaints have included fatigue.
• The patient's recent glucose tests indicate she is not doing well and that she has recently lost 30lbs and gained 10.
• A1C is 9.8% at the time of the most recent test and it showed high.

Therapy Adjustment Considerations

• She may still take a GLP-1, but basal insulin may be required along with SGLT2 Inhibitors.

Options for Basal Insulin

• Glargine - ~24 hrs (once a day).
• Detemir – 17 hr (bid).
• Degludec - >42 hrs (once a day).

Insulin Titration Information

• In Combination with semaglutide 1.0mg, metformin 1000mg, levels fell with the help of insulin glargine 25 units.
• After 1 year, gradual rise in glucose level shows levels increase in her bedtime glargine to 40 units.
• The patient shows signs of blurred vision, is fatigue, and experiences polyuria a recent value show 8.5%.

Basal Insulin

• Titration of basal insulin is done by looking at the change from HS values to AM values. If a change is not seen insulin dose should be looked at and adjusted accordingly.

Explore the progression and characteristics of type 2 diabetes. Understand metabolic abnormalities, hyperinsulinemic compensation, and disease stages. Learn effective interventions for pre-diabetes and management of long-standing diabetes.